IntelGenx Technologies Corp. (IGX) 2023年年度報告「TSX-V」.pdf

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1、UNITED STATESSECURITIES AND EXCHANGE COMMISSIONWashington,D.C.20549FORM 10-K ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934For the fiscal year ended December 31,2023 or TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d)OF THE SECURITIES EXCHANGE ACT OF 1934For the

2、 transition period from _ to _Commission file number 000-31187IntelGenx Technologies Corp.(Exact Name of Registrant as Specified in Its Charter)Delaware 87-0638336State or Other Jurisdiction ofIncorporation or Organization I.R.S.Employer Identification No.6420 Abrams,Ville Saint Laurent,Quebec,Canad

3、a H4S 1Y2Address of Principal Executive Offices Zip CodeRegistrants telephone number,including area code (514)331-7440Securities registered pursuant to Section 12(b)of the Act:NoneSecurities registered pursuant to Section 12(g)of the Act:Title of each classTrading Symbol(s)Name of each exchange on w

4、hich registeredCommon Stock,$0.00001 par valueIGXTIGXOTCQBTSXIndicate by check mark if the registrant is a well-known seasoned issuer,as defined in Rule 405 of the Securities Act.Yes No Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or 15(d)of the Act

5、.Yes No Indicate by check mark whether the registrant(1)has filed all reports required to be filed by Section 13 or 15(d)of the Securities Exchange Act of1934 during the preceding 12 months(or for such shorter period that the registrant was required to file such reports),and(2)has been subject to su

6、chfiling requirements for the past 90 days.Yes No Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405of Regulation S-T(232.405 of this chapter)during the preceding 12 months(or for such shorter period th

7、at the registrant was required to submit suchfiles).Yes No Indicate by check mark whether the registrant is a large accelerated filer,an accelerated filer,a non-accelerated filer,smaller reporting company,oran emerging growth company.See the definitions of large accelerated filer,accelerated filer,s

8、maller reporting company,and emerging growthcompany in Rule 12b-2 of the Exchange Act.Large accelerated filer Accelerated filer Non-accelerated filer Smaller reporting company Emerging growth company If an emerging growth company,indicate by check mark if the registrant has elected not to use the ex

9、tended transition period for complying with anynew or revised financial accounting standards provided pursuant to Section 13(a)of the Exchange Act.Indicate by check mark whether the registrant has filed a report on and attestation to its managements assessment of the effectiveness of its internalcon

10、trol over financial reporting under Section 404(b)of the Sarbanes-Oxley Act(15 U.S.C.7262(b)by the registered public accounting firm thatprepared or issued its audit report.If securities are registered pursuant to Section 12(b)of the Act,indicate by check mark whether the financial statements of the

11、 registrant included inthe filing reflect the correction of an error to previously issued financial statements.1Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensationreceived by any of the registrants executive

12、 officers during the relevant recovery period pursuant to 240.10D-1(b).1Indicate by check mark whether the registrant is a shell company(as defined in Rule 12b-2 of the Act).Yes No As of June 30,2023,the aggregate market value of the registrants voting and non-voting common equity held by non-affili

13、ates of the registrant was$23,983,889 based on the closing price of the registrants common stock of U.S.$0.19,as reported on the OTCQB on that date.Shares of the registrantscommon stock held by each officer and director and each person who owns 10%or more of the outstanding common stock of the regis

14、trant have beenexcluded in that such persons may be deemed to be affiliates.This determination of affiliate status is not necessarily a conclusive determination for otherpurposes.ClassOutstanding at March 21,2024Common Stock,$.00001 par value174,658,096 sharesIndicate the number of shares outstandin

15、g of each of the registrants classes of common stock,as of the latest practicable date.DOCUMENTS INCORPORATED BY REFERENCEPortions of the Companys Proxy Statement for its 2024 Annual Meeting of Shareholders(the 2024 Proxy Statement)are incorporated by reference into Part III _1 Not applicable.TABLE

16、OF CONTENTS Page PART I Item 1.Business.6Item 1ARisk Factors.36Item 1BUnresolved Staff Comments.46Item 1CCybersecurity46Item 2.Properties.47Item 3.Legal Proceedings.47Item 4.Mine Safety Disclosures.48 PART II 48 Item 5.Market for Registrants Common Equity,Related Stockholder Matters and Issuer Purch

17、ases of Equity Securities.48Item 6Selected Financial Data.52Item 7.Managements Discussion and Analysis of Financial Condition and Results of Operations.52Item 7AQuantitative and Qualitative Disclosures About Market Risk.64Item 8.Financial Statements and Supplementary Data.65Item 9.Changes in and Dis

18、agreements with Accountants on Accounting and Financial Disclosure.65Item 9A.Controls and Procedures.65Item 9B.Other Information.65 PART III66 Item 10.Directors,Executive Officers,and Corporate Governance.66Item 11.Executive Compensation.66Item 12.Security Ownership of Certain Beneficial Owners and

19、Management and Related Stockholder Matters.66Item 13.Certain Relationships and Related Transactions,and Director Independence.66Item 14Principal Accounting Fees and Services66 PART IV66 Item 15.Exhibits,Financial Statement Schedules66Item 16Form 10-K Summary Page66 Financial StatementsF-1-F-32Termin

20、ology and referencesIn this Annual Report on Form 10-K,the words Company,IntelGenx,we,us,and our,refer collectively to IntelGenx Technologies Corp.andIntelGenx Corp.,our wholly-owned Canadian subsidiary.In this Form 10-K,unless otherwise specified,all monetary amounts are in United States dollars,al

21、l references to$,U.S.$,U.S.dollars and dollarsmean U.S.dollars and all references to C$,Canadian dollars and CA$mean Canadian dollars.To the extent that such monetary amounts arederived from our consolidated financial statements included elsewhere in this Form 10-K,they have been translated into U.S

22、.dollars in accordance withour accounting policies as described therein.Unless otherwise indicated,other Canadian dollar monetary amounts have been translated into UnitedStates dollars at the average annual exchange rate for 2023 as reported by the Bank of Canada,being U.S.$1.00=CA$1.3497.PART ICaut

23、ionary Statement Concerning Forward-Looking StatementsCertain statements included or incorporated by reference in this report constitute forward-looking statements within the meaning of applicable securitieslaws.All statements contained in this report that are not clearly historical in nature are fo

24、rward-looking,and the words anticipate,believe,continue,expect,estimate,intend,may,plan,will,shall and other similar expressions are generally intended to identify forward-looking statementswithin the meaning of Section 27A of the United States Securities Act of 1933,as amended(Securities Act)and Se

25、ction 21E of the United StatesSecurities Exchange Act of 1934,as amended(Exchange Act).All forward-looking statements are based on our beliefs and assumptions based oninformation available at the time the assumption was made.These forward-looking statements are not based on historical facts but on m

26、anagementsexpectations regarding future growth,results of operations,performance,future capital and other expenditures(including the amount,nature and sourcesof funding thereof),competitive advantages,business prospects and opportunities and exchange listings.Forward-looking statements involve signi

27、ficantknown and unknown risks,uncertainties,assumptions and other factors that may cause our actual results,levels of activity,performance orachievements to differ materially from those implied by forward-looking statements.These factors should be considered carefully and prospectiveinvestors should

28、 not place undue reliance on the forward-looking statements.Although the forward-looking statements contained in this report orincorporated by reference herein are based upon what management believes to be reasonable assumptions,there is no assurance that actual results willbe consistent with these

29、forward-looking statements.These forward-looking statements are made as of the date of this report or as of the date specifiedin the documents incorporated by reference herein,as the case may be.We undertake no obligation to update any forward-looking statements toreflect events or circumstances aft

30、er the date on which such statements were made or to reflect the occurrence of unanticipated events,except as may be required by applicable securities laws.Forward-looking statements are subject to a variety of known and unknown risks,uncertainties and other factors which could cause actual events o

31、rresults to differ from those expressed or implied by the forward-looking statements,including,without limitation:risks related to our history of losses;risks related to the potential need for additional capital;risks related to the incurrence of unforeseen costs;risks related to our dependence on b

32、usiness partners for clinical trials,regulatory approvals and the marketing and selling of our products;the competition in our industry;the size and experience of our competitors;the laws,regulations and guidelines applicable to cannabinoid-based products;risks related to our dependence on suppliers

33、;risks related to the manufacturing of our VersaFilm products;risks related to regulatory approval and regulatory review of our products;our ability to expand or enhance our product offerings;the markets reception of our products that incorporate drug delivery technologies;risks related to environme

34、ntal regulations;the impact of COVID-19;risks related to the atai investment(as defined below);the risk the Investment is terminated;the restrictions on our business activities contained in the Securities Purchase Agreement(as defined below);that our existing shareholders(Shareholders)will have redu

35、ced ownership and voting interest if ATAI Life Sciences AG(atai)chooses toexercise their options to increase the Investment;the influence atai may have on our business;the risk that the Strategic Development Agreement(as defined below)may not result in commercially viable products;risks related to d

36、efault on our loan agreements;risks related to default on our convertible notes;risks related to the developments of compounds that have psychedelic,entactogenic and/or oneirophrenic properties;risks related to public controversy with respect to compounds that may contain controlled substances;our a

37、bility to adequately protect our intellectual property;the risk we infringe on the intellectual property rights of third parties;the risk that certain of our products may be subject to litigation;the risk of litigation in the ordinary course of business;risks related to cyber security and the protec

38、tion of our information systems;4risks related to the high risk nature of the common stock of the Company(the Common Stock);our failure to achieve and maintain profitability;actual or anticipated variations in our quarterly results of operations;the application of penny stock rules to our Common Sto

39、ck and its impact on trading and liquidity;the lack of public market for certain of our outstanding securities;the risk of dilution upon the conversion or exercise of outstanding securities;risks related to events of default with respect to our Debentures(as defined below)and Notes(as defined below)

40、;risks related to foreign currency fluctuations;the impact of securities analyst downgrades of our Common stock;andrisks associated with the prior activities of the public company we merged with.The factors set forth in Item 1A.,Risk Factors,as well as any cautionary language in this report,provide

41、examples of risks,uncertainties and eventsthat may cause our actual results to differ materially from the expectations we describe in our forward-looking statements.Before you invest in ourCommon Stock,you should be aware that the occurrence of the events described as risk factors and elsewhere in t

42、his report could have a materialadverse effect on our business,operating results and financial condition.5ITEM 1.BUSINESS.Corporate History Our predecessor company,Big Flash Corp.,was incorporated in Delaware on July 27,1999.On April 28,2006,Big Flash Corp.,through itsCanadian holding corporation,co

43、mpleted the acquisition of IntelGenx Corp.,a Canadian company incorporated on June 15,2003.The Company did nothave any operations prior to the acquisition of IntelGenx Corp.In connection with the acquisition,we changed our name from Big Flash Corp.to IntelGenxTechnologies Corp.IntelGenx Corp.has con

44、tinued operations as our operating subsidiary.OverviewWe are a drug delivery company established in 2003 and headquartered in Montreal,Quebec,Canada.Our focus is on the contractdevelopment and manufacturing of novel oral thin film products for the pharmaceutical market.More recently,we have made the

45、 strategic decision toenter the psychedelic market by entering into a strategic partnership with atai Life Sciences.The Company has applied and is operating under a CDMO business model:As a full service contract development and manufacturingorganization(CDMO),we are offering partners a comprehensive

46、 portfolio of pharmaceutical services,including pharmaceutical research anddevelopment(R&D),clinical monitoring,regulatory support,tech transfer,manufacturing scale-up and commercial manufacturing.Our businessstrategy is to leverage our proprietary drug delivery technologies and develop pharmaceutic

47、al products with tangible benefits for patients,for our partnersand,once a developed product launches,retain the exclusive manufacturing rights.We have undertaken a strategy under which we will work with pharmaceutical companies in order to apply our oral film technology topharmaceutical products fo

48、r which patent protection is nearing expiration,a strategy which is often referred to as lifecycle management.Under Section505(b)(2)of the Federal Food,Drug,and Cosmetics Act(the FDCA)(Section 505(b)(2),the U.S.Food and Drug Administration(the FDA)maygrant market exclusivity for a term of up to thre

49、e years following approval of a listed drug that contains previously approved active ingredients but isapproved in a new dosage,dosage form,route of administration or a combination.The Section 505(b)(2)pathway is also the regulatory approach to be followed if an applicant intends to file an applicat

50、ion for a product containinga drug that is already approved by the FDA for a certain indication and for which the applicant is seeking approval for a new indication or for a new use,the approval of which is required to be supported by new clinical trials,other than bioavailability studies.We have im

51、plemented a strategy under which weactively look for such so-called repurposing opportunities and determine whether our proprietary VersaFilm technology adds value to the product.Wecurrently have two such drug repurposing projects in our development pipeline.We continue to develop the existing produ

52、cts in our pipeline and may also perform R&D on other potential products as opportunities arise.We have established a state-of-the-art manufacturing facility with the intent to manufacture all of our VersaFilm products in-house as webelieve that this:represents a profitable business opportunity;will

53、 reduce our dependency upon third-party contract manufacturers,thereby protecting our manufacturing process know-how and intellectualproperty;andallows us to offer our clients and development partners a full service from product conception through to supply of the finished product.In order to succes

54、sfully execute our business strategy it will be essential to create and maintain a fully compliant manufacturing environment capable ofmeeting customer expectations regarding current Good Manufacturing Practices(cGMP)compliance and manufacturing capacity.Our website address is .6Technology Platforms

55、Our main product development efforts are based upon three delivery platform technologies:(1)VersaFilm,an oral film technology,(2)the VetaFilmTMtechnology platform for veterinary applications,and(3)DisinteQTM a disintegrating oral film technology.VersaFilm is a drug delivery platform technology that

56、enables the development of oral thin films,improving product performance through:rapid disintegration without the need for water;quicker buccal or sublingual absorption;potential for faster onset of action and increased bioavailability;potential for reduced adverse effects by bypassing first-pass me

57、tabolism;easy administration for patients who have problems swallowing tablets or capsules;pediatric and geriatric patients as well as patients who fearchoking and/or are suffering from nausea(e.g.,nausea resulting from chemotherapy,radiotherapy or any surgical treatment);pleasant taste;and small an

58、d thin size,making it convenient for consumers.Our VersaFilm technology consists of a thin(25-35 micron)polymeric film comprised of United States Pharmacopeia components that are approved bythe FDA for use in food,pharmaceutical,and cosmetic products.Derived from the edible film technology used for

59、breath strips and initially developed forthe instant delivery of savory flavors to food substrates,the VersaFilm technology is designed to provide a rapid response and improved bioavailabilitycompared to existing conventional tablets.Our VersaFilm technology is intended for indications requiring rap

60、id onset of action,such as migraine,opioiddependence,chronic pain,motion sickness,erectile dysfunction,and nausea or for drug that have a low oral bioavailability and require transmucosalabsorption.Our VetaFilm platform technology is designed for the application in companion animals.Dose acceptance

61、and compliance are often a challenge for thecare giver which can be overcome with our newly designed VetaFilm platform.VetaFilm is specifically formulated with flavors that are appealing topets and to achieve rapid adhesion to the oral mucosa of the animal to achieve compliance.Our new DISINTEQ oral

62、 disintegrating film formulations will provide different dissolution characteristics compared to VersaFilm.Instead of quicklydissolving in the oral cavity,DISINTEQ formulations disintegrate at a controlled rate.This will allow a slower release of the drug into the oral cavitythereby avoiding saturat

63、ion of the oral mucosal membranes and increasing mucosal absorption.Our Product PortfolioOur product portfolio includes a blend of generic and branded products based on our proprietary delivery technology(generic products areessentially copies of products that have already received FDA approval).Of

64、the eleven projects currently in our product portfolio,ten use our VersaFilmtechnology and one uses our VetaFilmTM technology.Our most advanced projects:INT0008/2008:We developed a Rizatriptan oral film product based on our VersaFilm technology.In March 2013 we submitted a Section505(b)(2)New Drug A

65、pplication(NDA)to the FDA for our novel oral thin-film formulation of Rizatriptan,which demonstrated to be bioequivalent to theactive drug in Maxalt-MLT orally disintegrating tablets.Maxalt-MLT is a leading branded anti-migraine product marketed by Merck&Co.The thin-filmformulation of Rizatriptan wa

66、s originally developed under a co-development and commercialization agreement with RedHill Biopharma Ltd.(RedHill)which was terminated December 5,2017,following which Redhill transferred all rights and obligations to us.On July 5,2016,we announced the signing of a definitive agreement with Grupo Jus

67、te S.A.Q.F.(now Exeltis Healthcare,S.L.(Exeltis)for thecommercialization of RIZAPORT for the treatment of acute migraines in Spain.Exeltis is a prominent private Spanish company with over 90 years ofexperience in the research,development and commercialization of proprietary pharmaceutical products,i

68、ncluding migraine and other central nervoussystem drugs,in Europe,Latin America and other territories.7Under the definitive agreement,Exeltis obtained exclusive rights to register,promote and distribute RIZAPORT in Spain.In exchange,the Companyand Redhill received upfront payments and are entitled t

69、o milestone payments,together with a share of the net sales of RIZAPORT in Spain.The initialterm of this agreement is ten years from the date of first commercial sale of the product and shall automatically renew for one additional two-year term.On August 27,2020,we announced that we had granted Exel

70、tis an exclusive license to manufacture and commercialize RIZAPORT in the EuropeanUnion(EU).Exeltis will pay us prespecified royalties on net RIZAPORT sales in the EU.In addition,we have a right of first refusal to manufacture thisproduct for the EU market.Effective September 9,2020,we signed a tech

71、nology transfer agreement with LTS Lohmann Therapy Systems for futuremanufacture and supply of the product for Spain.On December 14,2016,we announced the signing of an exclusive license agreement with Pharmatronic Co.for the commercialization ofRIZAPORT in the Republic of Korea(South Korea).Under th

72、e terms of such agreement,we granted Pharmatronic Co.the exclusive rights to registerand commercialize RIZAPORT in South Korea.IntelGenx received an upfront payment and will be eligible to receive additional milestone paymentsupon achievement of certain predefined regulatory and commercial targets,a

73、s well as tiered royalties.The initial term of the definitive agreement withPharmatronic Co.is for ten years from the date of first commercial sale and shall automatically renew for an additional two-year term.On October 31,2018,we received National marketing authorization from the Spanish Agency of

74、 Medicines and Medical Devices forRIZAPORT(10mg)in Spain.On December 12,2018,we announced the execution of a definitive licensing,development and supply agreement with Gensco Pharma,aspecialty pharmaceutical company focusing on research,development and marketing of prescription products,for the excl

75、usive right to commercializeRIZAPORT in the United States.In return,we are entitled to receive royalty payments based on the net profits of RIZAPORT.We are also eligible toreceive milestone payments upon FDA approval and product launch.This agreement also grants Gensco Pharma a right of first refusa

76、l for theexclusive rights to develop,market,sell,distribute and fully commercialize products as a partner for the Peoples Republic of China.On January 30,2019,we announced that the FDA had performed a Pre-Approval Inspection(PAI)of our manufacturing facility in Montreal,relating to our NDA for RIZAP

77、ORT.At the conclusion of the PAI on January 25,the FDA issued a Form 483 with five inspectional observations thatneeded attention before final approval.On March 27,2020,we received an additional complete response letter(CRL)from the FDA.The FDA requested additional information,but nonew bioequivalen

78、ce study.On September 7,2021,we announced that Exeltis,our commercialization partner in the EU for RIZAPORT,a unique for the treatment of acutemigraines,launched the product in Spain.On October 18,2022,we announced that we responded to the CRL received from the FDA.On November 22,2022,we announced t

79、hat the FDA had accepted for review its Class 2 response to the 2020 CRL and that the FDA hadassigned a Prescription Drug User Fee Act(PDUFA)goal date of April 17,2023 for completion of the review of the RIZAFILM NDA.(RIZAFILM is aRegistered Trademark of Gensco Pharma Corporation).On January 23,2023

80、,we announced that we entered into an exclusive supply agreement(the ARWAN Agreement)for RIZAPORT withARWAN Pharmaceuticals Industries Lebanon s.a.l.(ARWAN)in various countries in the Middle East and North Africa(MENA)region,includingLebanon,Kuwait,Saudi Arabia,United Arab Emirates,Jordan,Iraq,Libya

81、,Oman,Yemen,Qatar,Bahrain,Egypt,Sudan,Kenya,Nigeria,Mauritius,Cameroon,Afghanistan,Tajikistan,Kazakhstan,Turkmenistan,and Uzbekistan(the Territory).Under the terms of the ARWAN Agreement,IntelGenx will supply RIZAPORT to ARWAN,which will have the exclusive right to register andcommercialize it in th

82、e Territory.On April 17,2023,we announced that the FDA has approved the Companys RIZAFILM VersaFilm 505(b)(2)NDA for the treatment of acutemigraine.On September 21,2023,the Company announced that it received the first purchase order(PO)for RIZAFILM from its commercial partner inthe United States,Gen

83、sco Pharma(Gensco).On February 20,2024,IntelGenx confirmed the expected launch to occur in the second quarter.8INT0046/2018/INT55/2021:Our first cannabis project based on our VersaFilm technology contains 10mg CBD/CBDA.On November 7,2018 we announced the execution of a definitive license,development

84、 and supply agreement with Tilray,Inc.(Tilray),a globalleader in cannabis production and distribution.Under such agreement,the two companies will co-develop and commercialize oral film products infusedwith adult-used medical cannabis(cannabis infused VersaFilm).Under the agreement,the Company and Ti

85、lray will fund 20%and 80%,respectively,of the costs associated with the development of thecannabis infused Versafilm products.The Company will have the exclusive right to manufacture and supply the co-developed products to Tilray,andwill also receive a fixed single-digit royalty on net product sales

86、.Tilray will have the exclusive,worldwide marketing and distribution rights for the co-developed products.In connection with the Tilray agreement,the Company and Tilray also executed a subscription agreement under which Tilray made a strategicinvestment in IntelGenx through a non-brokered private pl

87、acement(the Tilray Private Placement).As a result,we issued Tilray 1,428,571 shares ofCommon Stock at a subscription price of$0.70 per share of Common Stock for gross proceeds of$1,000,000.We used the proceeds of the Tilray PrivatePlacement for cannabis infused VersaFilm product development under th

88、e agreement with Tilray.On May 2019,we received the first extract from Tilray in sufficient quantities to commence batch production of cannabis-infused VersaFilmfollowed by an announcement in October 2019 that the formulation had progressed to the scale-up manufacturing stage.The manufacturing scale

89、-upwork was completed successfully in January 2020.In the spring of 2019,we applied for a micro-processing license under the Canadian Cannabis Act(the Cannabis Act),which would allow us toprocess 600kg of cannabis per year,perform analytical testing and begin sales and research on cannabis.On June 5

90、,2020,we received the cannabismicro-processing license from Health Canada for our Montreal,Quebec facility,in accordance with the Cannabis Act and the regulations thereunder.On July 20,2020,we announced that the exclusivity terms of the November 2018 license,development and supply agreement with Til

91、ray hadbeen amended to allow for the Companys co-development and commercialization of cannabidiol(CBD)products with additional partners.Inconsideration,we shall pay a royalty to Tilray on all CBD products sold under this amendment.All other terms of such agreement,including thosepertaining to Tilray

92、s exclusive,worldwide marketing and distribution rights for non-CBD cannabis infused VersaFilm,remained unchanged.On October 29,2020,we signed a letter of intent with Heritage Cannabis Holding Corp.(Heritage Cannabis)for long term cannabis filmstripsupply agreement.Shortly after,on January 7,2021,we

93、 announced the execution of a definitive supply agreement with Heritage Cannabis for themanufacturing and supply of filmstrip products containing 10 mg of CBD/CBDA using our VersaFilm technology for the Canadian and Australianmarkets.On August 31,2021,we announced that we completed a shipment of CBD

94、/CBDA Filmstrips in support of Heritage Cannabis Canadian marketlaunch of its CB4 Control branded product.The product was subsequently successfully launched by Heritage Cannabis in Canada and the relationshipis ongoing between the parties.On December 8,2021,we announced that we initiated an arbitrat

95、ion proceeding against Tilray,related to an alleged breach of the parties 2018license,development and supply agreement,as amended with Tilray for the co-development and commercialization of cannabis-infused VersaFilmproducts.On November 6,2023,we announced that we entered into a further amendment(th

96、e Second Amendment)to the November 2018 license,development and supply agreement for the co-development and commercialization of cannabinoid-infused VersaFilm products,settling IntelGenxsarbitration claim against Tilray.Pursuant to the Second Amendment,IntelGenx has received an initial PO from Tilra

97、y for three SKUs(CBD20,THC10,THC10:CBD 10),with each SKU totalling 130,000 filmstrips.The Second Amendment also allows for IntelGenxs co-development and commercializationof CBD,THC,and combination THC:CBD products with additional partners.The Second Agreement removes any royalties paid to or from Ti

98、lray.9INT0007/2006:We are developing an oral film product based on our VersaFilm technology containing the active ingredient tadalafil.Thisproduct is intended for the treatment of erectile dysfunction(ED).The results of a phase I pilot study conducted in the second quarter of 2015 confirmedthat the

99、product is bioequivalent with the brand product,Cialis.On May 8,2019,we executed a worldwide collaboration agreement for tadalafil with Aquestive Therapeutics,Inc.(Aquestive).Under the termsof this agreement,the Company and Aquestive will each grant to the other exclusive worldwide licenses to their

100、 respective intellectual property relating totadalafil oral film formulation and manufacturing.The companies will jointly undertake further co-development and commercialization of tadalafil oral filmproducts,and will equally share(50/50)net profits from worldwide product sales.Aquestive previously s

101、ubmitted an NDA for its tadalafil oral film for thetreatment of ED to the FDA.In November 2018,Aquestive received a CRL from the FDA requesting additional safety data from healthy volunteers.Bothcompanies are currently working on responding to the CRL.On September 29,2021,we announced that Aquestive

102、,our co-development and commercialization partner for Tadalafil oral films for thetreatment of erectile dysfunction and benign prostatic hyperplasia,entered into a definitive license and supply agreement with an undisclosed leadingmens health company for the US.INT0039/2013:This product is based on

103、one of our proprietary technologies and was being developed under another development andcommercialization agreement with Par Pharmaceuticals(Par).On September 18,2015,Endo International plc(Endo)acquired Par.As a result of thisacquisition,Par had a conflict and was unable to remain as the partner f

104、or this product.Therefore,the product was returned to us with full rights and norequirement for any compensation for work paid by Par.On September 12,2016,we entered into a licensing,development and supply agreement with Chemo Group(Chemo)granting Chemo theexclusive license to commercialize two gene

105、ric products for the United States market and one product on a worldwide basis.Under the terms of thisagreement,Chemo obtained certain exclusive rights to market and sell our products in exchange for upfront and milestone payments,together with ashare of the profits of commercialization.Chemo also h

106、as a right of first negotiation to obtain the exclusive commercialization rights for two of theproducts to include any country outside the United States.On October 4,2018,we submitted an Abbreviated New Drug Application(ANDA)to the FDA for a generic buccal film product for our partner,Insud Pharma(f

107、ormerly Chemo Group).On January 30,2019,the FDA confirmed the acceptance for review of this ANDA with a GDUFA date ofOctober 18,2019.On June 2019,the FDA conducted a PAI for the buccal film that resulted in the FDA issuing us a Form 483,a report from an investigator notingconditions that in their ju

108、dgment may constitute violations of the FDCA and related acts.Further,in October 2019,we received a CRL in which the FDAdeclined to approve our product.A CRL does not necessarily indicate that a drug or biologic is not safe or effective.Rather,the FDA issues a CRL whenit has reviewed the submitted d

109、ata and has outstanding questions.A CRL allows the FDA to provide an applicant with a systematic list of deficienciesdetected within the submission package sent to the agency that stop short of requiring an entire resubmission.Our updated response to the Form 483was submitted on April 28 2021 and ou

110、r response to the CRL was sent to the FDA on May 14,2021.In February 2022,the FDA conducted a second PAIbased on the initial response to the CRL filed earlier in May 2021 which resulted in the issuance of a Form 483 with two observations.Subsequently,onMarch 14,2022 the FDA issued a second CRL reque

111、sting more information on the product and changes to the labellingOn October 25,2022,we announced that our previously undisclosed development candidate,Buprenorphine Buccal Film,for which anabbreviated ANDA has been filed by Chemo Research through its agent and affiliate Xiromed(Xiromed),has receive

112、d a U.S.FDA Generic Drug UserFee Act(GDUFA)date of April 28,2023.On April 27,2023,we announced that our co-developer,Chemo Research SL,through Xiromed,received a CRL from the FDA regarding thesubmitted ANDA for Buprenorphine Buccal Film.On September 19,2023,we provided a regulatory update on Bupreno

113、rphine Buccal Film,for which anANDA has been filed with the FDA by our co-developer,Chemo Research SL,through Xiromed.In response to the CRL,Xiromed submitted to the FDA an Amendment to the ANDA,requesting priority review.In an Amendment Acknowledgementreceived from the FDA by Xiromed,the FDA grante

114、d priority review with a Generic Drug User Fee Act(GDUFA)goal date for review of the Amendmentof March 8,2024,unless the Agency determines that an inspection is required.As of March 21,2024,Xiromed,is still in discussions with the FDAregarding the amended abbreviated new drug application submitted t

115、o the Agency in September.10INT0043/2015:We developed an oral film containing montelukast as the active ingredient based on our proprietary VersaFilm oral filmtechnology,which is in the early clinical trial phase.We are collaborating with Dr.Ludwig Aigner,a member of our Scientific Advisory Board an

116、d head of the Institute of Molecular RegenerativeMedicine at the Paracelsus Medical University in Salzburg,Austria.Dr.Aigner has made major contributions in the field of brain and spinal cordregeneration over the last 25 years.He was the first to develop tools to visualize neurogenesis in living ani

117、mals and identified crucial signalingmechanisms that are involved in limiting brain regeneration.One of these mechanisms,leukotriene signaling,is related to asthma.In consequence,Dr.Aigner and his team recently demonstrated that the anti-asthmatic drug montelukast structurally and functionally rejuv

118、enates the aged brain.His mainaim is to develop molecular and cellular therapies for patients with neurodegenerative diseases and for the aged population.On July 13,2016,we announced the successful completion of a pilot clinical study for our montelukast VersaFilm that demonstrated asignificantly im

119、proved pharmacokinetic profile compared to the reference product.The study data confirmed that buccal absorption of the drug from themontelukast film product resulted in a significantly improved bioavailability of the drug compared to the commercial tablet.In addition,the study dataconfirmed that mo

120、ntelukast crosses the blood brain barrier when administered using our Versafilm delivery technology.In 2017,we announced receiving a no objection letter from Health Canada regarding a Phase IIa proof-of-concept study.The objectives of this26-week,randomized,double-blind and placebo-controlled Phase

121、IIa proof of concept study to be conducted at eight clinical study sites across Canadawill be to evaluate the safety,feasibility,tolerability and efficacy of montelukast buccal film in patients with mild to moderate Alzheimers Disease(AD).The trial design includes testing of up to 70 patients.Based

122、on the outcome of this first efficacy trial in humans,we began actively seeking a partnershipor alliance opportunity to further advance developmental work and commercialization of this product.On September 25,2018,we announced the beginning of patient recruitment for the proposed AD study.In October

123、 2019,an independent DataSafety Monitoring Board(DSMB)completed its first interim analysis of the ongoing montelukast AD Phase IIa(BUENA)clinical trial in patients withmild to moderate AD.The DSMB reviewed compiled safety data from 25 subjects enrolled in the BUENA trial,13 of whom have completed 26

124、 weeks ofdaily treatment.The DSMB did not raise any concerns regarding safety and recommended that the trial continue.Based on additional efficacy testing of montelukast in an AD mouse model,conducted in collaboration with Prof.Dr.Ludwig Aigners group atthe Paracelsus Medical University in Salzburg

125、suggesting that montelukast,when given at higher doses,significantly improves cognition in patientssuffering from memory impairment and dementia,a revision of the dosage regiment was requested to Health Canada through the filing of a clinical trialapplication.Health Canada issued a non-objection let

126、ter in January 2020.On October 12,2021,we announced our intention to resume patient screening in the ongoing BUENA clinical trial in patients with mild tomoderate AD following Health Canadas issuance of a no objection letter in response to IntelGenxs amended Clinical Trial Application.On January 20,

127、2022,we announced that patient dosing has resumed in the ongoing BUENA clinical trial in patients with mild to moderate ADunder a previously amended protocol using higher doses of Montelukast VersaFilm.On September 8,2022,we announced that patient enrollment in the ongoing BUENA clinical trial in pa

128、tients with mild to moderate AD hadreached the halfway mark.Currently,this proof-of-concept study includes ten clinical research sites,all of which are expected to enroll a total of approximately 70 patients.On February 9,2023,IntelGenx announced a research collaboration with Per Svenningsson,MD,PhD

129、,of the Karolinska Institute,to plan andconduct a multicentre,randomized,double-blind,placebo-controlled clinical study(the PD Study)to investigate the use of IntelGenxs MontelukastVersaFilm for the treatment of Parkinsons Disease(PD).Dr.Svenningsson will serve as the Principal Investigator for the

130、planned Study and will sponsor it through a 20 million Swedish Crowns grant(approx.$2 million USD)awarded by the Swedish Research Council,Swedens largest governmental research funding body.IntelGenx will supply Dr.Svenningsson with both active and placebo films to be used in the 18-month treatment r

131、egimen for study participants.Upon completion of the Study,IntelGenx will retain the intellectual property rights and use the findings to further develop its Montelukast VersaFilm program for PD treatment.The PDStudy is currently expected to commence in the first half of 2024.11PD is one of the most

132、 common movement disorders in elderly people and is the second most common neurodegenerative disorder afterAlzheimers Disease(AD).It is a neurodegenerative disorder where misfolded alpha-synuclein-enriched aggregates,called Lewy bodies,are central inpathogenesis.No neuroprotective or disease-modifyi

133、ng treatments are currently available.The current standard treatment of PD motor dysfunction isbased on the enhancement of dopaminergic transmission and involves the administration of L-dopa.Evidence from multiple patient studies and animalmodels has shown a significant immune component during the c

134、ourse of the disease,highlighting immunomodulation as a potential treatment strategy.Montelukast is a CysLT1 antagonist which decreases neuroinflammation by inhibiting CysLT1.Early results have indicated its potential usefulness for thetreatment of various neurodegenerative disorders like PD and AD.

135、On July 25,2023,we announced the execution of a Research Grant Agreement with Karolinska University Hospital and that the manufacturingof both active and placebo films are underway in preparation for a planned multicentre,randomized,double-blind,placebo-controlled clinical PD Study toinvestigate the

136、 use of IntelGenxs Montelukast VersaFilm for the treatment of Parkinsons Disease(PD).On August 1,2023,we announced that we have completed patient enrollment in the ongoing Montelukast VersaFilm Phase 2a(BUENA)clinical trial in patients with mild to moderate AD.The Company successfully enrolled 52 pa

137、tients in the study,18 fewer than initially planned,in a studydesign modification that received a No Objection Letter(NOL)from Health Canada.The NOL provided authorization to proceed with the study changes.IntelGenx,in consultation with its statistical consultant,Cogstate Ltd.,determined that adjust

138、ing the p-value(which determines whether a drug effectexists)to p0.1 will provide a basis for determining the extent to which effect sizes(the size of the drug effect)of 0.6 or greater(0.5 to 0.8 areconsidered medium effect sizes,while 0.8 or greater are considered large effect sizes1)are statistica

139、lly significant.On November 14,2023,we announced that the Swedish Medical Products Agency(MPA),the Swedish Ethical Review Authority,and theRegional Biobank Centre have approved the planned clinical study to investigate the use of IntelGenxs Montelukast VersaFilm for the treatment of PD.Our Psychedel

140、ic Programs:INT0053/2020.On August 20,2020 we entered into a feasibility agreement with atai to develop pharmaceutical-grade polymeric film-basedpsychedelics.On October 13,2022,we provided an update on our collaboration with atai.Pursuant to the feasibility agreement,IntelGenx conducted pre-developm

141、ent,formulation development work and clinical supply manufacturing to provide a product prototype to atai for further clinical investigation.Thatpreviously undisclosed candidate,buccal VLS-01,is a buccal film containing a synthetic form of N,N-dimethyltryptamine.atai is developing the product asa no

142、vel therapy for treatment-resistant depression(TRD)in combination with atais digital therapeutic designed to provide contextual(mind)set-and-setting support to patients prior to dosing.On March 4,2024,Atai announced that the first healthy participant has been dosed in the Phase 1b trial of VLS-01,an

143、 oral transmucosal film(OTF)formulation of N,N-dimethyltryptamine(DMT).The Phase 1b study is designed to evaluate the relative safety,tolerability,pharmacokinetics andpharmacodynamics of an optimized OTF formulation of VLS-01,compared to intravenous(IV)DMT.This single center,open label study is anti

144、cipated toenroll a total of 16 healthy participants.Participants will initially receive a single dose of IV DMT followed by 3 different doses of VLS-01,with a 28-daywashout window between administrations.Top-line results for the Phase 1b study are expected in the second half of this year.INT0054/202

145、0.On May 12,2021,we entered into a second feasibility agreement with atai for the development of novel formulations ofSalvinorin A,a naturally occurring psychedelic compound being developed for the treatment of TRD and other indications.This program is discontinued.12Our Animal Health Programs:INT00

146、48/2020 VetaFilm:On January 9,2020 we entered the animal health market by signing a feasibility agreement for its VetaFilm platform.We have performed all of our obligations under such agreement and the successfully developed high loading VetaFilm which was sent for evaluation byour partner.Based on

147、the successful feasibility study,we are advancing the product development with the partner.On February 8,2021,we announced that we had filed a new provisional patent application at the United States Patent and Trademark Office(USPTO)entitled High Loading Oral Film Formulation.The patent application

148、covers the incorporation of high concentrations of active ingredients inproducts based on IntelGenxs VetaFilm proprietary veterinary oral film technology.This higher loading capability enables a formulation with a ratio ofactive-to-polymer of 1-to-1,thereby pushing the limit of the film capabilities

149、 and distinguishing it from known oral film technology.On December 18,2023,we announced that we entered into development and license agreements with a wholly-owned subsidiary of CovenantAnimal Health Partners,LLC(Covenant Animal Health).Under the terms of the development agreement,Covenant Animal He

150、alth will funddevelopment and manufacturing of a VetaFilm-based drug(the Product).The license agreement will give Covenant Animal Health exclusive rights toexploit the Product in the field for non-human applications.In return,IntelGenx will receive royalties on worldwide net sales of the Product.Int

151、elGenx willmanufacture the Product on a worldwide basis for clinical development,and the parties anticipate entering into a subsequent commercial supplyagreement,pursuant to which IntelGenx will supply the Product to Covenant Animal Health.On February 5,2024,we announced positive results from a proo

152、f-of-concept(POC)study to assess the palatability,owner-perceivedacceptability,and ease of repeated administration of IntelGenxs VetaFilm platform in healthy dogs and cats.The POC study was conducted through aresearch collaboration with the University Prince Edward Island(UPEI),one of North Americas

153、 leading veterinary universities.The reliableadministration of medications to dogs and cats is a concern for many owners and veterinarians.There are few prescribed medications that dogs and catswill eagerly accept.Forced administration of capsules,tablets and liquids may be stressful for both the pe

154、t and its owner(s).Additionally,many ownersreport that medicating their pet becomes more difficult with each dose,often leading to decreased owner compliance,missed doses and potentiallytreatment failures.IntelGenxs VetaFilm-based fast dissolving oral films(VetaFilm FDOFs)present a new and potential

155、ly superior way to medicatecompanion animals.The research collaboration with UPEI evaluated:(1)the acceptance rate of various VetaFilm placebo formulations in dogs and cats at firstexposure;(2)preference between flavours of VetaFilm placebo formulations in dogs and cats;(3)changes in acceptance rate

156、s over longer periods;and(4),owner perception of ease of administration,acceptance and other behaviors associated with VetaFilm placebo formulations.Key findings included:The VetaFilm FDOFs were well accepted and well tolerated by both dogs and cats;Repeated dosing(twice a day for one week)showed hi

157、gh continued acceptance rates in both species with little or no effect of time on thecontinued acceptance of the VetaFilm FDOFs;Overall,100%of dog owners and 67%of cat owners felt that administration of the VetaFilm FDOFs was very easy or easy;and 95%of dog owners and 82%of cat owners identified Vet

158、aFilm FDOFs as the preferred method of medication administration.Other Programs:INT0027/2011:We developed this oral film product based on our VersaFilm technology under a co-development and commercializationagreement with Par(now an operating company of Endo).The product is a generic formulation of

159、a commercial buprenorphine and naloxone-containingsublingual film for the treatment of opioid dependence.With Par,we developed a bioequivalent film formulation,scaled-up to a commercial manufacturingprocess and manufactured and tested pivotal batches during a subsequent pivotal clinical study.Par fi

160、led an ANDA with the FDA in July 2013.13On August 2013,we were notified that,in response to the filing of the ANDA,we were named as a co-defendant in a lawsuit under Paragraph IVof the Hatch-Waxman Act filed by Reckitt Benckiser Pharmaceuticals(Reckitt)and Monosol RX(Monosol)in the United States Dis

161、trict Court for theDistrict of Delaware(the Delaware Court)alleging infringement of United States Patent Nos.8,475,832,8,603,514 and 8,017,150,each of which relateto Suboxone.We believe the ANDA product does not infringe those or any other patents.Under the terms of the co-development andcommerciali

162、zation agreement,Par was financially responsible for the costs of the defense.In June 2016,the Delaware Court ruled that our product is notinfringing on two out of the three patents.Subsequently,both parties filed appeals.On December 2014,Reckitt and Monosol filed another lawsuit for patent infringe

163、ment in the Delaware Court relating to the Suboxone ANDAproduct.We were named as a co-defendant in this action alleging patent infringement of United States Patent Nos.8,900,497(the 497 patent)and8,906,277(the 277 patent),each of which related to a process for making a uniform oral film(the process

164、patents).The trial on the process patentswas held in November 2016.On May 14,2018,the Company,Par,Indivior,Inc.,Indivior UK Limited,and Aquestive(previously Monosol RX)settled all patent litigation relatedto Suboxone film.The settlement agreement permitted Par to begin selling a generic version of S

165、uboxone film on January 1,2023.The project ispresently on hold.INT0036/2013:This oral film product is based on our proprietary oral film technology VersaFilm.Loxapine is indicated for the treatment ofanxiety and aggression in patients suffering from schizophrenia or bipolar 1 disorder.Using our Vers

166、aFilm technology allows an improved product tooffer patients significant therapeutic benefits compared to existing medications.We expect to effectively treat acute agitation associated withschizophrenia or bipolar 1 disorder in non-institutionalized patients while reducing the risk of pulmonary prob

167、lems.Our product offers an importanttherapeutic benefit to these patients,as it could substantially reduce the potential risks of violence and injury to patients and others by preventing orreducing the duration and severity of an episode of acute agitation.Our first clinical study on this product,co

168、mpleted in the fourth quarter of 2014,suggested improved bioavailability compared to the currently approved tablet.In late 2015,we completed a second pilot clinical study whichdemonstrated that buccal absorption of the drug from the Loxapine oral film results in a significantly higher bioavailabilit

169、y of the drug compared to oraltablets.We were working to optimize the film to further improve the time to reach peak plasma concentrations,however,due to the prioritization of ourproject line,we directed resources to other projects,leading to a temporary hold of the optimization work during 2019.Thi

170、s project is currently on hold.On February 21,2023,IntelGenx announced that the USPTO granted a Notice of Allowance for U.S.Patent Application 16/053,383,entitledLoxapine Film Oral Dosage Form.This film formulation patent covers Loxapine oral film formulations designed for use in patients with anxie

171、ty andagitation associated with schizophrenia and bipolar 1 disorder,and is intended to protect IntelGenx Loxapine VersaFilm product.INT0010/2006:This product is based on our proprietary AdVersa technology and has been transferred to Tetra BioPharma.We initially enteredinto an agreement with Cynapsu

172、s Therapeutics Inc.(formerly Cannasat Therapeutics Inc.,Cynapsus)for the development of a buccal muco-adhesivetablet product containing a cannabinoid-based drug for the treatment of neuropathic pain and nausea in cancer patients undergoing chemotherapy.In2009,we completed a clinical biostudy on this

173、 product.The study results indicated improved bioavailability and reduced first-pass metabolization of thedrug.In the fourth quarter of 2010,we acquired full control of,and interest in,this project from Cynapsus going forward.We also obtained worldwiderights to United States Patent 7,592,328 and all

174、 corresponding foreign patents and patent applications to exclusively develop and further secureintellectual property protection for this project.On October 21,2020,we entered into an amended and restated licensing agreement with Tetra Bio-Pharma under which Tetra purchased theworldwide Adversa tech

175、nology rights as it relates to its PPP-002(Dronabinol)drug product candidate for three undisclosed milestone payments:45%tobe paid on November 15,2020;45%to be paid on March 1,2021,and a final payment of 10%upon successful technology transfer.In addition,Tetra willpay us a royalty on future net sale

176、s of Dronabinol mucoadhesive tablets.14The current status of each of our products as of the date of this Annual Report is summarized in the table below.ProductIndicationStatus of DevelopmentINT0008/2008MigraineLaunched in Spain and Launch preparationfor US marketINT0046/2018 andINT0055/2021Adult Use

177、Launched CanadaINT0007/2006Erectile dysfunctionWorking on response to Aquestives CRLINT0039/2013PainPending FDA approvalINT0027/2011Opioid addictionCurrently on holdINT0043/2015Alzheimer/ParkinsonsBUENA Study enrollment completed anddata under analysis.PD study approved by MPA,enrollment inpreparati

178、onINT0010/2006Treatment of neuropathic pain and nausea in cancer patientsundergoing chemotherapyTransferred to TetraBioINT0036/2013Schizophrenia or bipolar 1 disorderCurrently on holdINT0048/2020Animal HealthClinical StudyINT0053/2020Treatment resistant depression(TRD)Clinical Study Growth StrategyO

179、ur primary growth strategy is based on providing CDMO services to the pharmaceutical industry.We have established a state-of-the-art manufacturing facility for the future manufacture of our VersaFilm and VetaFilm products.We believe that this(1)represents a profitable business opportunity,(2)will re

180、duce our dependency upon third-party contract manufacturers,thereby protecting ourmanufacturing process know-how and intellectual property,and(3)allows us to offer our development partners a full service from product conceptionthrough to supply of the finished product.With our current manufacturing

181、equipment,we are only able to manufacture products that do not contain flammable organic solvents.We initiated aproject to expand the existing manufacturing facility,the timing of which will be dictated in part by the completion of agreements with our commercialpartners.This expansion became necessa

182、ry following requests by commercial partners to increase manufacturing capacity and provide solvent filmmanufacturing capabilities.The new facility should create a fivefold increase of our production capacity in addition to offering a one-stop shoppingopportunity to our partners and provide better p

183、rotection of our Intellectual Property.Product Opportunities that provide Tangible Patient BenefitsWe offer our services to develop oral film products leveraging our VersaFilm technology that provide tangible patient benefits versus existing drugdelivery forms.Patients with difficulties swallowing m

184、edication,pediatrics or geriatrics may benefit from oral films due to the ease of use.Similarly,we areworking on oral films to improve bio-availability and/or response time versus existing drugs and thereby reducing side effects.We have also identified theAnimal Health sector,particularly the compan

185、ion animal segment,as an area where our proprietary oral film technology can significantly improve theadministration of medication to animals.Development of New Drug Delivery TechnologiesThe rapidly disintegrating film technology contained in our VersaFilm is an example of our efforts to develop alt

186、ernate technology platforms.As we workwith various partners on different products,we seek opportunities to develop new proprietary technologies.15CompetitionThe pharmaceutical industry is highly competitive and is subject to the rapid emergence of new technologies,governmental regulations,healthcare

187、legislation,availability of financing,patent litigation and other factors.Many of our competitors,including Aquestive(formerly Monosol Rx),Tesa-LabtecGmbH,Collegium Pharmaceutical Inc.(formerly BioDelivery Sciences International,Inc.)and LTS Lohmann Therapy Systems Corp.,have longeroperating histori

188、es and greater financial,technical,marketing,legal and other resources than we have.In addition,many of our competitors havesignificantly greater experience than we have in conducting clinical trials of pharmaceutical products,obtaining FDA and other regulatory approvals ofproducts,and marketing and

189、 selling products that have been approved.We expect that we will be subject to competition from numerous other companiesthat currently operate or are planning to enter the markets in which we compete.The key factors affecting the development and commercialization of our drug delivery products are li

190、kely to include,among other factors:the regulatory requirements;the safety and efficacy of our products;the relative speed with which we can develop products;generic competition for any product that we develop;our ability to defend our existing intellectual property and to broaden our intellectual p

191、roperty and technology base;our ability to differentiate our products;our ability to develop products that can be manufactured on a cost effective basis;our ability to manufacture our products in compliance with cGMP and any other regulatory requirements;andour ability to obtain financing.In order t

192、o establish ourselves as a viable full service CDMO partner,we plan to continue to invest in our R&D activities,analytical testing and in ourmanufacturing technology expertise,in order to further strengthen our technology base and to develop the ability to manufacture products based on ourdrug deliv

193、ery technologies at competitive costs.Our Competitive StrengthsWe believe that our key competitive strengths include:our comprehensive service portfolio;our ability to swiftly develop products through to regulatory approval;the versatility of our drug delivery technologies,and our highly qualified,d

194、edicated professional team.Dependence on Major CustomersWe currently rely on a few major customers for our end products.We also currently depend upon a limited number of partners to develop ourproducts,to provide funding for the development of our products,to assist in obtaining regulatory approvals

195、 that are required in order to commercializethese products,and to market and sell our products.16Intellectual Property and Patent ProtectionWe protect our intellectual property and technology by using the following methods:(i)applying for patent protection in the United States and inthe appropriate

196、foreign markets,(ii)non-disclosure agreements,license agreements and appropriate contractual restrictions and controls on thedistribution of information,and(iii)trade secrets,common law trademark rights and trademark registrations.We plan to file core technology patentscovering the use of our platfo

197、rm technologies in any pharmaceutical products.We have obtained 39 patents and have 43 published pending patent applications,as described below.The patents expire 20 years aftersubmission of the initial application.In the United States,the term of a patent sometimes extends over the 20-year period.T

198、he initial term of 20 years isextended by a period(the patent term adjustment)determined by the USPTO according to delays in the prosecution of the patent application that arenot applicant delays.Our patent portfolio is dynamic in nature and constantly under review to assess the business priorities,

199、as such any of the currently pendingapplication and issued patent may be abandoned if the expense of pursuing prosecution or maintaining the patent or application active is no longerwarranted by our business targets.Patent No.TitleSubjectDate issued/Expiration US 7,674,479Sustained-release bupropion

200、 andbupropion/mecamylamine tabletsFormulation and method of makingtablets containing bupropion andmecamylamineIssued March 9,2010Expires July 25,2027 US 8,691,272Multilayer tabletFormulation of multilayered tablets Issued April 8,2014Expires January 28,2033 US 8,703,191Controlled release pharmaceuti

201、caltabletsFormulation of tablets containingbupropion and mecamylamineIssued April 22,2014Expires January 10,2032 US 8,735,374Oral mucoadhesive dosage formDirect compression formulation forbuccal and sublingual dosage formsIssued May 27,2014Expires April 15,2032 South Africa2016/00785Immediately wet

202、oral films dosageforms have no surfactant and apolyhydric alcoholFormulation of oral films containingactive pharmaceutical ingredientsFiled January 24,2017Expires July 30,2034 US 9,301,948Instantly wettable oral film dosageform without surfactant orpolyalcoholFormulation of oral films containingacti

203、ve pharmaceutical ingredientsIssued April 5,2016Expires July 30,2033 US 9,668,970Film Dosage Form with ExtendedRelease Mucoadhesive ParticlesFilm containing mucoadhesiveparticleIssued June 6,2017Expires November 26,2034 US 9,717,682 Solid Oral Film Dosage Forms andMethods for Making SameOptimization

204、 of film strip technologyIssued August 1,2017Expires September 21,2031 US 9,949,934Device and method of treatingconditions associated withneuroinflammationFormulation of oral films containingmontelukastIssued April 24,2018Expires October 20,2036 US 10,272,038 Film dosage form with extendedrelease mu

205、coadhesive particlesFilm containing mucoadhesiveparticleIssued April 30,2019Expires November 26,2034 17 US 10,610,528 Solid oral film dosage forms andmethods for making same Formulation of oral films containingtadalafil Issued April 7,2020Expires June 28,2031 US 10,722,476 Device and method of treat

206、ingconditions associated withneuroinflammation Formulation of oral films containingmontelukast Issued July 28,2020Expires October 20,2036 US 10,828,254 Oral film formulation for modulatingabsorption profile Formulation of oral films containingtadalafil Issued November 10,2020Expired September 28,203

207、8 CA 2,998,223 Loxapine film oral dosage form Formulation of oral films containingloxapine Issued October 9,2018Expires January 25,2037 CL 61.052 Instantly wettable oral film dosageform without surfactant orpolyalcohol Formulation of oral films containingactive pharmaceutical ingredients Issued Octo

208、ber 13,2020Expires July 30,2034JP 6,482,552 Instantly wettable oral film dosageform without surfactant orpolyalcohol Formulation of oral films containingactive pharmaceutical ingredients Issued February 22,2019Expires July 30,2034MX 366,595 Instantly wettable oral film dosageform without surfactant

209、orpolyalcohol Formulation of oral films containingactive pharmaceutical ingredients Issued July 15,2019Expires July 30,2034 CN 105530921 Instantly wettable oral film dosageform without surfactant orpolyalcohol Formulation of oral films containingactive pharmaceutical ingredients Issued February 26,2

210、021Expires July 30,2034 Germany602014034391.0 Instantly wettable oral film dosageform without surfactant orpolyalcohol Formulation of oral films containingactive pharmaceutical ingredients Issued October 17,2018Expires July 30,2034 Belgium3027179 Instantly wettable oral film dosageform without surfa

211、ctant orpolyalcohol Formulation of oral films containingactive pharmaceutical ingredients Issued October 17,2018Expires July 30,2034 Switzerland3027179 Instantly wettable oral film dosageform without surfactant orpolyalcohol Formulation of oral films containingactive pharmaceutical ingredients Issue

212、d February 26,2021Expires July 30,2034 18 Denmark3027179 Instantly wettable oral film dosageform without surfactant orpolyalcohol Formulation of oral films containingactive pharmaceutical ingredients Issued February 11,2019Expires July 30,2034 Spain3027179 Instantly wettable oral film dosageform wit

213、hout surfactant orpolyalcohol Formulation of oral films containingactive pharmaceutical ingredients Issued October 17,2018Expires July 30,2034 Finland3027179 Instantly wettable oral film dosageform without surfactant orpolyalcohol Formulation of oral films containingactive pharmaceutical ingredients

214、 Issued October 17,2018Expires July 30,2034 France3027179 Instantly wettable oral film dosageform without surfactant orpolyalcohol Formulation of oral films containingactive pharmaceutical ingredients Issued October 17,2018Expires July 30,2034 UK3027179 Instantly wettable oral film dosageform withou

215、t surfactant orpolyalcohol Formulation of oral films containingactive pharmaceutical ingredients Issued October 17,2018Expires July 30,2034Greece3027179 Instantly wettable oral film dosageform without surfactant orpolyalcohol Formulation of oral films containingactive pharmaceutical ingredients Issu

216、ed October 17,2018Expires July 30,2034 Italy502019000003967 Instantly wettable oral film dosageform without surfactant orpolyalcohol Formulation of oral films containingactive pharmaceutical ingredients Issued October 17,2018Expires July 30,2034Netherlands3027179 Instantly wettable oral film dosagef

217、orm without surfactant orpolyalcohol Formulation of oral films containingactive pharmaceutical ingredients Issued October 17,2018Expires July 30,2034 NorwayNO/EP3027179 Instantly wettable oral film dosageform without surfactant orpolyalcohol Formulation of oral films containingactive pharmaceutical

218、ingredients Issued October 17,2018Expires July 30,2034 Sweden3027179 Instantly wettable oral film dosageform without surfactant orpolyalcohol Formulation of oral films containingactive pharmaceutical ingredients Issued October 17,2018Expires July 30,2034 US 11,033,493 Film dosage form with extendedr

219、elease mucoadhesive particles Film containing mucoadhesiveparticle Issued June 15,2021Expires November 26,2038 19 CA 2998218 Device and method of treatingconditions associated withneuroinflammation Formulation of oral films containingmontelukast Issued June 15,2021Expires October 17,2037 KR102272442

220、 Instantly wettable oral film dosageform without surfactant orpolyalcohol Formulation of oral films containingactive pharmaceutical ingredients Issued June 28,2021Expires July 30,2034 US 11,471,406Oral film formulation for modulatingabsorption profile Formulation of oral films containinghydroxyethyl

221、 celluloseIssued October 18,2022Expires November 11,2038 BR112016002074-0 Instantly wettable oral film dosageform without surfactant orpolyalcohol Formulation of oral films containingactive pharmaceutical ingredients Issued January 24,2023Expires July 30,2034 US 11,602,504 Lipophilic active oral fil

222、m formulationand method of making the same Film containing lipophilicactives Issued March 14,2023Expires April 15,2039 US 11,648,212 Loxapine film oral dosage form Formulation of oral films containingloxapine Issued May 16,2023Expires October 12,2037 EP 3528796 Method of treating conditionsassociate

223、d with neuroinflammation Formulation of oral films containingmontelukast Issued February 7,2023Expires October 16,2037 Patent Application No.TitleSubjectDate Filed Chinese Appl.201780062591.7 The device and method for treatingillness relevant to neuroinflammation Formulation of oral films containing

224、montelukast Filed October 17,2017 Chinese Appl.201880016281.6 The treatment method and device ofthe bioavailability of improvedleukotriene receptor antagonists Formulation of oral films containingmontelukast Filed March 29,2018 Mexican Appl.MX2018010755 Montelukast transmucosal film Formulation of o

225、ral films containingmontelukast Filed March 1,2017 20 Mexican Appl.MX/A/2018/009306 Loxopine film oral dosage form Formulation of oral films containingloxapine Filed January 25,2017 Mexican Appl.MX/A/2019/004096 Device and method of treatingconditions associated withneuroinflammation Formulation of

226、oral films containingmontelukast Filed October 17,2017 Canadian Appl.CA3,017,264 Montelukast transmucosal film Formulation of oral films containingmontelukast Filed March 1,2017 Canadian Appl.CA3,017,526 Method of treatment and device forthe improved bioavailability ofleukotriene receptor antagonist

227、s Formulation of oral films containingmontelukast Filed September 14,2018 Canadian Appl.CA3,056,944 Method of treatment and device forthe improved bioavailability ofleukotriene receptor antagonists Formulation of oral films containingmontelukast Filed March 29,2018 Canadian Appl.CA 3,062,704 Film do

228、sage form with extendedrelease mucoadhesive particles Film containing mucoadhesiveparticle Filed May 8,2018 EP Appl.18798869.6 Film dosage form with extendedrelease mucoadhesive particles Film containing mucoadhesiveparticle Filed May 8,2018 Canadian Appl.CA 3,061,086 Lipophilic active oral film for

229、mulationand method of making the same Film containing lipophilic actives Filed November 6,2019 Canadian Appl.CA 3,122,192 Device and method of treatingconditions associated withneuroinflammation Formulation of oral films containingmontelukast Filed October 17,2017 US Appl.16/391,430 Film Dosage Form

230、s ContainingAmorphous Active Agents Film containing amorphousagent Filed April 23,2019 EP Appl.19859079 Method of treatment and device forthe improved bio availability ofmontelukast,a leukotriene receptorantagonist Formulation of oral films containingmontelukast Filed September 12,2019 Canadian Appl

231、.CA 3,118,594 Lipophilic active oral film formulationand method of making the same Formulation of oral films containinglipophilic actives Filed November 4,2019 21 EP Appl.19883191.9 Lipophile aktive oralefilmformulierung und verfahren zuihrer herstellung Formulation of oral films containinglipophili

232、c actives Filed November 4,2019 US Appl.17/291,582 Lipophilic active oral film formulationand method of making the same Formulation of oral films containinglipophilic actives Filed November 4,2019 US Appl.17/346,874 Film dosage form with extendedrelease mucoadhesive particles Film containing mucoadh

233、esiveparticles Filed June 14,2021 Australia Appl.2019374172 Lipophilic active oral film formulationand method of making the same Formulation of oral films containinglipophilic actives Filed November 4,2019 Canadian Appl.CA 3,150,213 Method of treatment and device forthe improved bio availability ofm

234、ontelukast,a leukotriene receptorantagonist Formulation of oral films containingmontelukast Filed September 12,2019 Mexican Appl.MX2021005292 Lipophilic active oral film formulationand method of making the same Formulation of oral films containinglipophilic actives Filed November 4,2019 PCT/CA2022/0

235、50171 High loading oral film formulationFormulation of oral films containing ahigh amount of actives Filed February 7,2022 PCT/CA2022/050212 Novel tryptamine oral film formulation Formulation of oral films containingtryptamine Filed February 14,2022 US Appl.US 17/842,372 Stable Tryptamine Oral Films

236、Formulation of oral films containingtryptamineFiled June 16,2022 US Appl.US 17/732,456 Method Of Treatment And DeviceFor The Improved Bioavailability OfLeukotriene Receptor Antagonists Formulation of oral films containingmontelukastFiled April 28,2022 US Appl.US 17/729,442 Method Of Treatment And De

237、viceFor The Improved Bioavailability OfLeukotriene Receptor Antagonists Formulation of oral films containingmontelukastFiled April 26,2022 22 New Zealand Appl.NZ 775442Lipophilic active oral film formulationand method of making the sameFormulation of oral films containinglipophilic activesFiled Nove

238、mber 4,2019 Australia Appl.2022217673High loading oral film formulationFormulation of oral films for highloadingFiled February 7,2022 Brazil Appl.BR112023015504-5High loading oral film formulationFormulation of oral films for highloadingFiled February 7,2022 Canadian Appl.3,207,185High loading oral

239、film formulationFormulation of oral films for highloadingFiled February 7,2022 Chinese Appl.202280013364.6High loading oral film formulationFormulation of oral films for highloadingFiled February 7,2022 Israel Appl.304928High loading oral film formulationFormulation of oral films for highloadingFile

240、d February 7,2022 Japan Appl.2023-547033High loading oral film formulationFormulation of oral films for highloadingFiled February 7,2022 Mexico Appl.MX/a/2023/009141High loading oral film formulationFormulation of oral films for highloadingFiled February 7,2022 New Zealand Appl.802249High loading or

241、al film formulationFormulation of oral films for highloadingFiled February 7,2022 South Korea Appl.10-2023-7028927High loading oral film formulationFormulation of oral films for highloadingFiled February 7,2022 EPO Appl.22748777.4High loading oral film formulationFormulation of oral films for highlo

242、adingFiled February 7,2022 23 US Appl.17/952,300 Oral film formulation for modulatingabsorption profileFormulation of oral films containingtadalafil Filed September 25,2022US Appl.18/098,683 Oral films with flavor entrapmentFormulation of oral films with flavortechnologyFiled January 18,2022US Appl.

243、18/110,879 Lipophilic active oral film formulationand method of making the same Formulation of oral films containinglipophilic activesFiled February 16,2023 US Appl.18/125,800 Method of preparing loxapine filmoral dosage form Methods for loxapine oral filmsFiled March 24,2023US Appl.18/208,177 Novel

244、 disintegrating oral filmformulation with a controlled orsustained active release Formulation of oral films forsustained active releaseFiled June 9,2023PCT/CA2023/051069 High loading oral film formulationwith improved bioavailabilityImprovements on formulation of oralfilms for high loading Filed Aug

245、ust 10,2023Government RegulationThe pharmaceutical industry is highly regulated.The products we participate in developing require certain regulatory approvals.In the UnitedStates,drugs are subject to rigorous regulation by the FDA.The FDCA,and other federal and state statutes and regulations,govern,

246、among other things,the research,development,testing,manufacture,storage,record keeping,packaging,labeling,adverse event reporting,advertising,promotion,marketing,distribution,and import and export of pharmaceutical products.Failure to comply with applicable regulatory requirements may subject acompa

247、ny to a variety of administrative or judicially-imposed sanctions and/or the inability to obtain or maintain required approvals or to market drugs.Thesteps ordinarily required before a new pharmaceutical product may be marketed in the United States include:preclinical laboratory tests,animal studies

248、 and formulation studies under FDAs good laboratory practices regulations,(GLPs);the submission to the FDA of an investigational new drug application,which must become effective before human clinical trials may begin;the completion of adequate and well-controlled clinical trials according to good cl

249、inical practice regulations,(GCPs),to establish the safety andefficacy of the product for each indication for which approval is sought;after successful completion of the required clinical testing,submission to the FDA of an NDA,or an ANDA,for generic drugs.In certain cases,an application for marketi

250、ng approval may include information regarding safety and efficacy of a proposed drug that comes from studies notconducted by or for the applicant.Such applications,known as a Section 505(b)(2)NDA,are permitted for new drug products that incorporatepreviously approved active ingredients,even if the p

251、roposed new drug incorporates an approved active ingredient in a novel formulation or for anew indication;24satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which the product is to be produced,toassess compliance with cGMPs to assure that the f

252、acilities,methods and controls are adequate to preserve the drugs identity,strength,qualityand purity;andFDA review and approval of the NDA or ANDA.The cost of complying with the foregoing requirements,including preparing and submitting an NDA or ANDA,may be substantial.Accordingly,wetypically rely

253、upon our partners in the pharmaceutical industry to spearhead and bear the costs of the FDA approval process.We also seek to mitigateregulatory costs by focusing on Section 505(b)(2)NDA opportunities.By applying our drug delivery technology to existing drugs,we seek to developproducts with lower R&D

254、 expenses and shorter time-to-market timelines as compared to regular NDA products.The preclinical and clinical testing and approval process takes many years and the actual time required to obtain approval,if any,may varysubstantially based upon the type,complexity and novelty of the product or dise

255、ase.Preclinical tests include laboratory evaluation of product chemistry,formulation and toxicity,as well as animal studies to assess thecharacteristics and potential safety and efficacy of the product.The conduct of the preclinical tests must comply with federal regulations andrequirements,includin

256、g GLPs.The results of preclinical testing are submitted to the FDA as part of an Investigational New Drug(IND)application alongwith other information,including information about product chemistry,manufacturing and controls and a proposed clinical trial protocol.Long-termpreclinical tests,such as ani

257、mal tests of reproductive toxicity and carcinogenicity,may continue after the IND application is submitted.The IND application automatically becomes effective 30 days after receipt by the FDA,unless the FDA,within the 30-day time period,raisesconcerns or questions relating to one or more proposed cl

258、inical trials and places the clinical trial on a clinical hold,including concerns that humanresearch subjects will be exposed to unreasonable health risks.In such a case,the IND sponsor and the FDA must resolve any outstanding concernsbefore the clinical trial can begin.A separate submission to an e

259、xisting IND application must also be made for each successive clinical trial conductedduring product development.Further,an independent institutional review board(IRB),covering each site proposing to conduct the clinical trial mustreview and approve the plan for any clinical trial and informed conse

260、nt information for subjects before the trial commences at that site and it must monitorthe study until completed.The FDA,the IRB,or the sponsor may suspend a clinical trial at any time on various grounds,including a finding that thesubjects or patients are being exposed to an unacceptable health ris

261、k or for failure to comply with the IRBs requirements,or may impose otherconditions.Clinical trials involve the administration of the investigational new drug to healthy volunteers or patients under the supervision of a qualifiedinvestigator in accordance with GCP requirements,which includes the req

262、uirement that all research subjects provide their informed consent in writing fortheir participation in any clinical trial.Sponsors of clinical trials generally must register and report,at the NIH-maintained website ClinicalTrials.gov,keyparameters of certain clinical trials.For purposes of an NDA s

263、ubmission and approval,human clinical trials are typically conducted in the followingsequential phases,which may overlap or be combined:In Phase 1,through the initial introduction of the drug into healthy human subjects or patients,the drug is tested to assess metabolism,pharmacokinetics,pharmacolog

264、ical actions,side effects associated with increasing doses,and,if possible,early evidence on effectiveness.Phase 2 usually involves trials in a limited patient population to determine the effectiveness of the drug for a particular indication,dosagetolerance and optimum dosage,and to identify common

265、adverse effects and safety risks.Phase 3 trials are undertaken to obtain the additional information about clinical efficacy and safety in a larger number of patients,typically atgeographically dispersed clinical trial sites,to permit the FDA to evaluate the overall benefit-risk relationship of the d

266、rug and to provide adequateinformation for the labeling of the drug.In most cases,the FDA requires two adequate and well controlled Phase 3 clinical trials to demonstrate theefficacy of the drug.A single Phase 3 trial with other confirmatory evidence may be sufficient in rare instances where the stu

267、dy is a large multicenter trialdemonstrating internal consistency and a statistically persuasive finding of a clinically meaningful effect on mortality,irreversible morbidity or prevention ofa disease with a potentially serious outcome and confirmation of the result in a second trial would be practi

268、cally or ethically impossible.After completion of the required clinical testing,an NDA is prepared and submitted to the FDA.FDA approval of the NDA is required beforemarketing of the product may begin in the United States.The NDA must include the results of all preclinical,clinical and other testing

269、 and a compilation ofdata relating to the products pharmacology,chemistry,manufacture and controls.Under federal law,the submission of most NDAs is subject to asubstantial application user fee,and applicant under an approved NDA is also subject to an annual program fee for each prescription drug pro

270、duct,which beginning in Fiscal Year 2018 replaced the product and establishment fees.25The FDA has 60 days from its receipt of an NDA to determine whether the application will be accepted for filing based on the agencys thresholddetermination that it is sufficiently complete to permit substantive re

271、view.The FDA may request additional information rather than accept an NDA forfiling.In this event,the NDA must be resubmitted with the additional information and is subject to payment of additional user fees.The resubmittedapplication is also subject to review before the FDA accepts it for filing.On

272、ce the submission is accepted for filing,the FDA begins an in-depthsubstantive review.Under the Prescription Drug User Fee Act,the FDA has agreed to certain performance goals in the review of NDAs through a two-tiered classification system,Standard Review and Priority Review.Priority Review designat

273、ion is given to drugs that offer major advances in treatment orprovide a treatment where no adequate therapy exists.The FDA endeavors to review applications subject to Standard Review within ten to twelvemonths,whereas the FDAs goal is to review Priority Review applications within six to eight month

274、s.The FDA may refer applications for proprietary drug products or drug products which present difficult questions of safety or efficacy to anadvisory committee for review,evaluation and recommendation as to whether the application should be approved and under what conditions.Before approving an NDA,

275、the FDA will typically inspect one or more clinical sites to assure compliance with GCP requirements.Additionally,theFDA will inspect the facility or the facilities at which the drug is manufactured.The FDA will not approve the product unless it determines that themanufacturing process and facilitie

276、s are in compliance with cGMP requirements and are adequate to assure consistent production of the product withinrequired specifications and the NDA contains data that provide substantial evidence that the drug is safe and effective in the indication studied.After the FDA evaluates the NDA and the m

277、anufacturing facilities and possibly conducts a sponsor inspection,it issues either an approval letteror a complete response letter.A complete response letter generally outlines the deficiencies in the NDA and may require substantial additional testing,orinformation,in order for the FDA to reconside

278、r the application.Even with submission of this additional information,the FDA may ultimately decide that anapplication does not satisfy the regulatory criteria for approval.If,or when,the deficiencies have been addressed to the FDAs satisfaction in aresubmission of the NDA,the FDA will issue an appr

279、oval letter.The review by the FDA is two months for a Class I resubmission and six months for aClass 2 resubmission.An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.As a condition of NDA approval,the FDA may require a REMS,

280、or Risk Evaluation and Mitigation Strategy,to help ensure that the benefits of thedrug outweigh the potential risks.If the FDA determines a REMS is necessary during review of the application,the drug sponsor must agree to theREMS plan at the time of approval.A REMS may be required to include various

281、 elements,such as a medication guide or patient package insert,acommunication plan to educate healthcare providers of the drugs risks,limitations on who may prescribe or dispense the drug,or other elements toassure safe use,such as special training or certification for prescribing or dispensing,disp

282、ensing only under certain circumstances,special monitoringand the use of patient registries.In addition,the REMS must include a timetable to periodically assess whether the REMS plan is effective.Therequirement for a REMS can materially affect the potential market and profitability of a drug.Moreove

283、r,product approval may require substantial post-approval testing and surveillance to monitor the drugs safety or efficacy,and the FDAhas the authority to prevent or limit further marketing of a product based on the results of these post-marketing programs.Once granted,productapprovals may be withdra

284、wn if compliance with regulatory standards is not maintained or problems are identified following initial marketing.Drugs may bemarketed only for the approved indications and in accordance with the provisions of the approved label,and,even if the FDA approves a product,it maylimit the approved indic

285、ations for use for the product or impose other conditions,including labeling or distribution restrictions or other risk-managementmechanisms.Further changes to some of the conditions established in an approved application,including changes in indications,labeling,or manufacturingprocesses or facilit

286、ies,require submission and FDA approval of a new NDA or NDA supplement before the change can be implemented,which mayrequire us to develop additional data or conduct additional preclinical studies and clinical trials.An NDA supplement for a new indication typically requiresclinical data similar to t

287、hat in the original application,and the FDA uses similar procedures in reviewing NDA supplements as it does in reviewing NDAs.26Post-Approval RequirementsOngoing adverse event reporting and submission of periodic reports are required following FDA approval of an NDA.The FDA also may requirepost-mark

288、eting testing,known as Phase 4 testing,REMS,and surveillance to monitor the effects of an approved product,or the FDA may placeconditions on an approval that could restrict the distribution or use of the product.In addition,quality control,drug manufacture,packaging,and labelingprocedures must conti

289、nue to conform to cGMPs and NDA specifications after approval.Drug manufacturers and certain of their subcontractors arerequired to register their establishments with FDA.Accordingly,manufacturers must continue to expend time,money,and training and compliance effortsin the areas of production and qu

290、ality control to maintain compliance with cGMPs or other applicable laws.Regulatory authorities may requireremediation,withdraw product approvals or request product recalls if a company fails to comply with regulatory standards,if it encounters problemsfollowing initial marketing,or if previously un

291、recognized problems or new concerns are subsequently discovered.In addition,other regulatory action,including,among other things,warning letters,the seizure of products,injunctions,consent decrees placing significant restrictions on or suspendingmanufacturing operations,civil penalties,and criminal

292、prosecution may be pursued.The Hatch-Waxman AmendmentsANDA Approval ProcessThe Hatch-Waxman Amendments established abbreviated FDA approval procedures for drugs that are shown to be equivalent to drugspreviously approved by the FDA through its NDA process.Approval to market and distribute these drug

293、s is obtained by submitting an ANDA to the FDA.An ANDA is a comprehensive submission that contains,among other things,data and information pertaining to the active pharmaceutical ingredient,drug product formulation,specifications and stability of the generic drug,as well as analytical methods,manufa

294、cturing process validation data and qualitycontrol procedures.Premarket applications for generic drugs are termed abbreviated because they generally do not include preclinical and clinical data todemonstrate safety and effectiveness.Instead,a generic applicant must demonstrate that its product is bi

295、oequivalent to the innovator drug.In certainsituations,an applicant may obtain ANDA approval of a generic product with a strength or dosage form that differs from a referenced innovator drugpursuant to the filing and approval of an ANDA Suitability Petition.The FDA will approve the generic product a

296、s suitable for an ANDA application if it findsthat the generic product does not raise new questions of safety and effectiveness as compared to the innovator product.A product is not eligible forANDA approval if the FDA determines that it is not equivalent to the referenced innovator drug,if it is in

297、tended for a different use,or if it is not subject toan approved Suitability Petition.However,such a product might be approved under an NDA,with supportive data from clinical trials.Section 505(b)(2)NDAsAs an alternative path to FDA approval for modifications to formulations or uses of products prev

298、iously approved by the FDA,an applicant maysubmit an NDA under Section 505(b)(2).Section 505(b)(2)was enacted as part of the Hatch-Waxman Amendments and permits the filing of an NDAwhere at least some of the information required for approval comes from studies not conducted by,or for,the applicant.I

299、f the Section 505(b)(2)applicantcan establish that reliance on FDAs previous findings of safety and effectiveness is scientifically appropriate,it may eliminate the need to conduct certainpreclinical or clinical studies of the new product.The FDA may also require companies to perform additional stud

300、ies or measurements,including clinicaltrials,to support the change from the approved branded reference drug.The FDA may then approve the new product candidate for all,or some,of thelabel indications for which the branded reference drug has been approved,as well as for any new indication sought by th

301、e Section 505(b)(2)applicant.Orange Book ListingIn seeking approval for a drug through an NDA,including a Section 505(b)(2)NDA,applicants are required to list with the FDA certain patentswith claims that cover the applicants product.Upon approval of an NDA,each of the patents listed in the applicati

302、on for the drug is then published in theOrange Book.Any applicant who files an ANDA seeking approval of a generic equivalent version of a drug listed in the Orange Book or a Section 505(b)(2)NDA referencing a drug listed in the Orange Book must certify to the FDA that(i)no patent information on the

303、drug product that is the subject of theapplication has been submitted to the FDA;(ii)such patent has expired;(iii)the date on which such patent expires;or(iv)such patent is invalid or will notbe infringed upon by the manufacture,use or sale of the drug product for which the application is submitted.

304、This last certification is known as aparagraph IV certification.A notice of the paragraph IV certification must be provided to each owner of the patent that is the subject of the certificationand to the holder of the approved NDA to which the ANDA or Section 505(b)(2)application refers.The applicant

305、 may also elect to submit a section viiistatement certifying that its proposed label does not contain(or carves out)any language regarding the patented method-of-use rather than certify to alisted method-of-use patent.27If the reference drug NDA holder and patent owners assert a patent challenge dir

306、ected to one of the Orange Book listed patents within 45 days ofthe receipt of the paragraph IV certification notice,the FDA is prohibited from approving the application until the earlier of 30 months from the receipt ofthe paragraph IV certification,expiration of the patent,settlement of the lawsui

307、t or a decision in the infringement case that is favorable to the applicant.The ANDA or Section 505(b)(2)application also will not be approved until any applicable non-patent exclusivity listed in the Orange Book for the brandedreference drug has expired as described in further detail below.Non-Pate

308、nt ExclusivityIn addition to patent exclusivity,the holder of the NDA for the listed drug may be entitled to a period of non-patent related exclusivity,duringwhich the FDA cannot review,or in some cases,approve an ANDA or Section 505(b)(2)application that relies on the listed drug.For example,acompa

309、ny may obtain five years of non-patent exclusivity upon NDA approval of a new chemical entity(NCE),which is a drug that contains an activemoiety that has not been approved by the FDA in any other NDA.An active moiety is defined as the molecule or ion responsible for the drugsubstances physiological

310、or pharmacologic action.During the five-year exclusivity period,the FDA cannot accept for filing any ANDA seeking approval ofa generic version of that drug or any Section 505(b)(2)NDA for the same active moiety and that relies on the FDAs findings regarding that drug,exceptthat FDA may accept an app

311、lication for filing after four years if the follow-on applicant makes a paragraph IV certification.A drug,including one approved under Section 505(b)(2),may obtain a three-year period of exclusivity for a particular condition of approval,orchange to a marketed product,such as a new formulation of a

312、previously approved product,if one or more new clinical studies(other than bioavailabilityor bioequivalence studies)was essential to the approval of the application and was conducted/sponsored by the applicant.Should this occur,the FDAwould be precluded from approving any ANDA or Section 505(b)(2)ap

313、plication for the protected modification until after that three-year exclusivity periodhas run.However,unlike NCE exclusivity,the FDA can accept an application and begin the review process during the exclusivity period.International RegulationIn addition to regulations in the United States,we are an

314、d will be subject to a variety of foreign regulations regarding development,approval,commercial sales and distribution of our products.Whether or not we obtain FDA approval for a product,we must obtain the necessary approvals by thecomparable regulatory authorities of foreign countries before we can

315、 commence clinical trials or marketing of the product in those countries.The approvalprocess varies from country to country and can involve additional product testing and additional review periods,and the time may be longer or shorterthan that required to obtain FDA approval.The requirements governi

316、ng,among other things,the conduct of clinical trials,product licensing,pricing andreimbursement vary greatly from country to country.Regulatory approval in one country does not ensure regulatory approval in another,but a failure ordelay in obtaining regulatory approval in one country may negatively

317、impact the regulatory process in others.If we fail to comply with applicable foreignregulatory requirements,we may be subject to fines,suspension or withdrawal of regulatory approvals,product recalls,seizure of products,operatingrestrictions and criminal prosecution.In the EU,we may seek marketing a

318、uthorization under either the centralized authorization procedure or nationalauthorization procedures.Centralized procedure.The European Medicines Agency,(EMA),implemented the centralized procedure for the approval of human medicinesto facilitate marketing authorizations that are valid throughout th

319、e EU.This procedure results in a single marketing authorization issued by the EuropeanCommission following a favorable opinion by the EMA that is valid across the European Union,as well as Iceland,Liechtenstein and Norway.Thecentralized procedure is compulsory for human medicines that are:derived fr

320、om biotechnology processes,such as genetic engineering,contain a newactive substance indicated for the treatment of certain diseases,such as HIV/AIDS,cancer,diabetes,neurodegenerative disorders or autoimmunediseases and other immune dysfunctions,and officially designated orphan medicines.For medicin

321、es that do not fall within these categories,an applicanthas the option of submitting an application for a centralized marketing authorization to the EMA,as long as the medicine concerned is a significanttherapeutic,scientific or technical innovation,or if its authorization would be in the interest o

322、f public health.National authorization procedures.There are also two other possible routes to authorize medicinal products in several EU countries,which areavailable for investigational medicinal products that fall outside the scope of the centralized procedure:the decentralized procedure and the mu

323、tualrecognition procedure.Under the decentralized procedure,an applicant may apply for simultaneous authorization in more than one EU country formedicinal products that have not yet been authorized in any EU country and that do not fall within the mandatory scope of the centralized procedure.Under t

324、he mutual recognition procedure,a medicine is first authorized in one EU Member State,in accordance with the national procedures of thatcountry.Following a national authorization,the applicant may seek further marketing authorizations from other EU countries under a procedure wherebythe countries co

325、ncerned agree to recognize the validity of the original,national marketing authorization.28In the EU,medicinal products designated as orphan products benefit from financial incentives such as reductions in marketing authorizationapplication fees or fee waivers and 10 years of market exclusivity foll

326、owing medicinal product approval.For a medicinal product to qualify as orphan:(i)itmust be intended for the treatment,prevention or diagnosis of a disease that is life-threatening or chronically debilitating;(ii)the prevalence of thecondition in the EU must not be more than five in 10,000 or it must

327、 be unlikely that marketing of the medicine would generate sufficient returns to justifythe investment needed for its development;and(iii)no satisfactory method of diagnosis,prevention or treatment of the condition concerned can beauthorized,or,if such a method exists,the medicine must be of signifi

328、cant benefit to those affected by the condition.Other RegulationWe are also subject to various laws and regulations regarding laboratory practices,the experimental use of animals,and the use and disposal ofhazardous or potentially hazardous substances in connection with our research.While we believe

329、 we are in compliance with applicable environmentaland other regulations,in each of these areas,as above,the FDA and other government agencies have broad regulatory and enforcement powers,including,among other things,the ability to levy fines and civil penalties,suspend or delay issuance of approval

330、s,seize or recall products,and withdrawapprovals,any one or more of which could have a material adverse effect on us.Canadian Medical and Adult-UseMedical and adult-use cannabis in Canada is regulated under the federal Cannabis Act and the Cannabis Regulations(CR)promulgated underthe Cannabis Act.Bo

331、th the Cannabis Act and CR came into force in October 2018,superseding earlier legislation that only permitted commercialdistribution and home cultivation of medical cannabis.The following are the highlights of the current federal legislation:a federal license is required for companies to cultivate,

332、process and sell cannabis for medical or non-medical purposes;Health Canada,federal government entity,is the oversight and regulatory body for cannabis licenses in Canada.As of December 31,2020,Health Canada has issued approximately 570 active licenses to licensees under the CR(Licensed Producers);a

333、llows individuals to purchase,possess and cultivate limited amounts of cannabis for medical purposes and,for individuals over the ageof 18 years,for adult-use recreational purposes;enables the provinces and territories to regulate other aspects associated with recreational adult-use.In particular,each province orterritory may adopt its own laws governing the distribution,sale and consumption of ca