2. Cheaper Drugs Today And Better Drugs Tomorrow History The industry’s lobbying efforts were well-timed. In the late 1970s, the U.S. economy was in recession and the Carter administration needed to create more jobs, the chair of the House Health Subcommittee, Henry Waxman, began promoting the bill as an opportunity to improve the country’s healthcare system. To that end, he touted the social benefits that could result from restoring the patent terms to certain pharmaceutical inventions and allowing companies to prepare to market generic drugs before the corresponding pioneer patents expired. Senator Orrin Hatch joined in, stating that enactment of the bill would be a ground- breaking compromise in the public interest in which the public receives the best of both worlds—cheaper drugs today and better drugs tomorrow. However, it was not until after the CAFC(court of appeals for federal circuits) handed down the Roche decision when Congress was able to rally behind what is now known as the Hatch-Waxman Act.

3. The Act can be divided into three main categories. The first part relates to drug price competition. Specifically, the legislation provides for an Abbreviated New Drug Application (ANDA) to be implemented by the U.S. Food and Drug Administration (FDA). Briefly, the ANDA provisions allow makers of generic drugs to apply for regulatory approval of their drugs if the drug hasn’t been patented, the patent term of the subject drug has expired, the patent will expire before the generic goes on the market, or the patent is invalid or not infringed.

4. The second part of the Act relates to patent term restoration. Briefly, this section provides that inventors of pioneer drugs may have their patent terms extended by an amount of time equal to one-half of the FDA’s investigational new drug period. The maximum term of extension is five years, but the effective market exclusivity may not exceed fourteen years. The third part of the Act, relates to the research exemption to patent infringement. Specifically, 35 U.S.C. § 271(e)(1) states, “ It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention (other than a new animal drug or veterinary biological product (as those terms are used in the Federal Food, Drug, and Cosmetic Act and the Act of March 4, 1913) which is primarily manufactured using recombinant DNA, recombinant RNA, hybridoma technology, or other processes involving site specific genetic manipulation techniques) solely for uses reasonably

5. -related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products." This part of the Act has been the subject of much controversy. In the context of Roche, it would appear that the main reason :- That Section 271(e)(1) was enacted was so that generic drug manufacturers could enter their products into the marketplace as soon as the corresponding pioneer patents expire. However, because of the ambiguous language of the statute and equally unclear legislative history, there has been considerable debate as to the scope of this statutory exemption as discussed below.

6. Hatch-Waxman Generic Manufacturers permitted to use safety and effectiveness data submitted by Brand companies need only demonstrate chemical and biological equivalence may begin testing before the patent on the proprietary drug expires first generic company to file an ANDA gets 180 days of “exclusivity Under Hatch-Waxman, the marketing approval process for generic drug products is streamlined.

7.  Full name- Drug Price Competition and Patent Term Restoration Act  Enacted in 1984  Purpose of the act-dual balancing act  Effect on the pharmaceutical industry Hatch-Waxman Act Today Many top-selling prescription drugs in the US are currently the subject of patent challenges by generic firms seeking to enter market under the Hatch-Waxman Act: — Singulair — asthma/allergy drug — Lovenox — deep vein thrombosis / pulmonary embolism — Abilify — schizophrenia, bipolar, and depression drug

8. DEFINITIONS:- It is considered as the landmark legislation which established the modern system of generic drugs in USA. Hatch-Waxman amendment of the federal food, drug and cosmetics act established the process by which, would be marketers of generic drugs can file Abbreviated New Drug Application (ANDA) to seek FDA approval of generic drugs. Paragraph IV of the act, allows 180 day exclusivity to companies that are the "first-to- file" an ANDA against holders of patents for branded counterparts.

9. In simple words  “Hatch-Waxman act is the amendment to Federal, Food, Drug and Cosmetics act which established the modern system of approval of generics through Abbreviated New Drug Applications (ANDAs)”  Amongst the aims of the Hatch-Waxman Act of 1984 was that of encouraging generic companies to challenge patents and gain early market entry. As explained in an earlier article, the compensation for this was to be a 180-day exclusivity period for the first generic company that was brave enough to file a Paragraph IV application to register.

10. Market exclusivity New chemical entities (NCE) 505(b)(1) or New Drug Applications Contains full reports of investigations of safety and effectiveness Five year exclusivity 505(b)(2) Application At least some of the information required for approval comes from studies not conducted by or for the applicant 180 days Market Exclusivity Section 505(j)(5)(B)(IV) First to file When does it start Judgment trigger Commercial marketing trigger

11. Salient Features Of The Act Patent challenges and generic exclusivity Patent term extension Exemption to infringement Prior to the Hatch and Waxman act the generic drug manufacturer had to do the entire clinical trials. After the passage of Hatch and Waxman act the generic drug manufacturer had to only prove bioequivalence of generic drug to the innovator drug by showing that the generic drug is 80-125% bioequivalent to the innovator drug. Patent challenges and generic exclusivity Patent term extension Exemption to infringement Prior to the Hatch and Waxman act the generic drug manufacturer had to do the entire clinical trials. After the passage of Hatch and Waxman act the generic drug manufacturer had to only prove bioequivalence of generic drug to the innovator drug by showing that the generic drug is 80-125% bioequivalent to the innovator drug.

12. The time and cost involved for getting the generic drug into the market was significantly reduced. Low cost quality, safe and effective generic drugs were available to the patients. Since 1984, over 10,000 generic drugs have entered the market, and generics accounted for close to 50 percent of prescriptions filled (as on august 1, 2003). Billions of dollars in health care costs are being saved annually. Generic drug approval process isn’t less complicated as it involves patent and exclusivity issues. If any New Molecular Entity (NME) is approved. It is granted a exclusivity period of 5 years, which could be extended to 3 more years for supplements requiring clinical trials.

13. Patent Certifications As per the Hatch and Waxman act, generic drug and 505 (b) (2) applicants should include certifications in their applications for each patent listed in the “Orange Book” for the innovator drug. This certification must state one of the following:  (I) that the required patent information relating to such patent has not been filed (Para I certification);  (II) that such patent has expired (Para II certification);  (III) that the patent will expire on a particular date (Para III certification); or  (IV) that such patent is invalid or will not be infringed by the drug, for which approval is being sought(Para IV certification). A certification under paragraph I or II permits the ANDA to be approved immediately, if it is otherwise eligible. A certification under paragraph III indicates that the ANDA may be approved when the patent expires.

14.  A paragraph IV certification, however, begins a process in which the question of whether the listed patent is valid or will be infringed by the proposed generic product may be answered by the courts before the expiration of the patent.  Under the current regulations, the ANDA applicant who files a paragraph IV certification to a listed patent must notify the patent owner and the NDA holder for the listed drug that it has filed an ANDA containing a patent challenge.  Until the effective date of FDA’s final rule, all patents submitted and listed in the Orange Book that are the subject of a paragraph IV certification require notice to the NDA holder and patent owner.  The notice must include a detailed statement of the factual and legal basis for the ANDA applicant’s opinion that the patent is not valid or will not be infringed.

15.  The submission of an ANDA for a drug product claimed in a patent is an infringing act if the generic product is intended to be marketed before expiration of the patent.  Accordingly, the ANDA applicant who submits an application containing a paragraph IV certification may be sued for patent infringement.  If the NDA holder or patent owner files a patent infringement suit against the ANDA applicant within 45 days of the receipt of notice, FDA may not give final approval to the ANDA for at least 30 months from the date of that notice.  This 30-month stay will delay approval of the generic drug product unless the court reaches a decision earlier in the patent infringement case or otherwise orders a longer or shorter period for the stay.

16. Key Terms of the Hatch-Waxman Amendments Streamlined generic approval process “Safe Harbor” for pre-approval activities Patent term restoration to offset lengthy regulatory approval process Non-patent exclusivity for innovators and generics Framework for patent notification and litigation ANDA – An abbreviated new drug application used to seek approval of a generic drug product. Paragraph IV Certification – The brand-name company’s patents are invalid or not infringed by the ANDA. Orange Book – The FDA’s listing of patents that claim brand-name drug products.

17. 30-Month Stay – A 30-month stay of FDA approval of an ANDA is invoked if a brand-name company receives notice of the generic applicant’s ANDA that contains a paragraph IV certification and files suit for patent infringement within 45-days of that notice. 180-Day Marketing Exclusivity – The first generic applicant to file an ANDA containing a paragraph IV certification is awarded 180-days of marketing exclusivity, upon its commercial marketing or a court decision, during which the FDA may not approve a subsequent generic applicant’s ANDA for the same drug product.

18. Balancing Innovation with Affordability “….the American people will save money, and yet receive the best medicine that pharmaceutical science can provide.” President Reagan, Sept. 24, 1984 “ MAJOR CERTIFICATIONS OF HWA“ “That patent information on the drug has not been filed i.e. no patent information appears in the orange book. That the patent has already expired. The date on which the patent will expire. That the patent is invalid or will not be infringed by the manufacture, use or sale of the drug for which the ANDA is submitted”. These certifications are termed as paragraph I, II, III, and IV certifications respectively.

19. Key Features of the Hatch-Waxman Act Streamlined generic approval process “Safe Harbor” for pre-approval activities Patent term restoration to offset lengthy regulatory approval process Non-patent exclusivity for innovators and generics Framework for patent notification and litigation

20. Requirements for generic approval Same active ingredient(s) Same route of administration Same dosage form Same strength Same conditions of use Compared to reference listed drug (RLD) - (brand name product)

21. Requirements for generic approval NDA 1.Chemistry 2.Manufacturing 3.Controls 4.Labeling 5.Testing 6.Animal Studies 7.Clinical Studies 8.Bioavailability ANDA 1.Chemistry 2.Manufacturing 3.Controls 4.Labeling 5.Testing 6.Bioequivalence

22. Key Features of the Hatch-Waxman Act Streamlined generic approval process “Safe Harbor” for pre-approval activities Patent term restoration to offset lengthy regulatory approval process Non-patent exclusivity for innovators and generics Framework for patent notification and litigation

23. “Safe Harbor” for pre-approval activities before the Act, a generic manufacturer who used a patented drug during the patent term for the purpose of conducting tests to submit information to the FDA committed patent infringement 35 U.S.C. § 271 (e)(1): It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention... solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.  Merck KGaA v. Integra Lifesciences I, Ltd., 545 U.S. 193 (2005)  statutory text “provides a wide berth for the use of patented drugs in activities related to the federal regulatory process”  use of patented compounds in preclinical studies is protected... as long as there is a reasonable basis for believing that the experiments will produce “the types of information that are relevant to an IND or NDA.”

24. Key Features of the Hatch-Waxman Act Streamlined generic approval process “Safe Harbor” for pre-approval activities Patent term restoration to offset lengthy regulatory approval process Non-patent exclusivity for innovators and generics Framework for patent notification and litigation

25. Patent Term Restoration  Formula Under 35 USC §156:  50% of the time spent in initial clinical trials (IND); PLUS  100% of the time spent in new drug application (NDA) approval process  Other Requirements:  No more than 5 years or up to 14 years from date of FDA approval  Patent not expired  No previous extension under this provision  First permitted commercial marketing or use  NOT the same as Patent Term Adjustment under § 154 (delays in PTO review)  Extension is in addition to any adjustment under § 154

26. Key Features of the Hatch-Waxman Act Streamlined generic approval process “Safe Harbor” for pre-approval activities Patent term restoration to offset lengthy regulatory approval process Non-patent exclusivity for innovators and generics Framework for patent notification and litigation

27. Innovator Non-Patent Exclusivity  Exclusivity Regardless of Existence of Patent  NCE (New Chemical Entity): 5 years  New active ingredient, new molecules, new salts  FDA can’t even accept a generic application for 5 years (4 years if a PIV challenge)  Effectively 7 ½ years if there is a PIV challenge after 4 years  New product/new use /supplemental exclusivity: 3 years  (new clinical studies to support a new indication, formulation, salt, dosage regimen, etc.; enantiomers)  Exclusivity Regardless of Existence of Patent  Orphan Drug: 7 years  If FDA approval is for disease affecting less than 200,000 U.S. citizens  Pediatric use: 6 months in addition to existing exclusivity or patent term  If pediatric study is undertaken in response to FDA written request

28. Key Features of the Hatch-Waxman Act Streamlined generic approval process “Safe Harbor” for pre-approval activities Patent term restoration to offset lengthy regulatory approval process Non-patent exclusivity for innovators and generics Framework for patent notification and litigation

29.  NDA holder must notify FDA of any patent that claims a drug or method of using a drug and with respect to which a claim of infringement can reasonably be asserted  FDA publishes in “Orange Book” Active Ingredient Search Results from "OB_Rx" table for query on “Rosuvastatin." Appl No TE Code RL D Active Ingredient Dosage Form; Route Strength Proprietary Name Applicant 021366No ROSUVASTATIN CALCIUM TABLET; ORAL 10MGCRESTORIPR 021366No ROSUVASTATIN CALCIUM TABLET; ORAL 20MGCRESTORIPR 021366Yes ROSUVASTATIN CALCIUM TABLET; ORAL 40MGCRESTORIPR 021366No ROSUVASTATIN CALCIUM TABLET; ORAL 5MGCRESTORIPR

30. Patent and Exclusivity Search Results from query on Appl No 021366 Product 002 in the OB_Rx list. Patent Data Appl No Prod No Patent No Patent Expiration Drug Substance Claim Drug Product Claim Patent Use Code Delist Requested 0213660026316460Aug 4, 2020Y 0213660026858618Dec 17, 2021U-618 021366002RE37314Jan 8, 2016Y Exclusivity Data Appl NoProd NoExclusivity CodeExclusivity Expiration 021366002NCEAug 12, 2008 021366002I-573Nov 6, 2011 021366002I-547Nov 8, 2010

31. Generic applicant patent certifications ANDA Certification Paragraph I: Paragraph II: Paragraph III: Paragraph IV: Patent status No Patent info in Orange Book Patent expired No product launch until patent expires Patent is invalid,unenforceable, or will not be infringed by the manufacture, use, or sale of the drug product for which the ANDA is submitted

32. Generic exclusivity First ANDA filer with Para. IV certification gets:  180 days of exclusivity against other generics  Starts with first marketing or final appeals court decision Notice Letter  Generic applicant who files a paragraph IV certification must notify the patent and NDA holder with a detailed statement  Patent/NDA holder has 45 days to sue  Generic applicant can file a declaratory judgment action if not sued

33. ADDITIONAL INFORMATION ON THE HATCH WAXMAN ACT Some additional information about the HWA as given below: The 30-month stay is permitted only once, in case of those patents listed in the Orange Book, when an ANDA is filed under paragraph IV certification. Modifications to the 30-month stay are allowed based on district court judgments. The generic drug manufacturers filing ANDA under paragraph IV are required to submit full and complete information over and above what is necessary under current law and must notify the patent owner within 20 days. If the patent owner does not file infringement proceeding within 45 days of notification issued by ANDA applicant, the applicant may request for a declaratory judgment and thus avoid being sued. Even if the applicant is sued, applicant may file a counter claim requiring patent owner to make changes in the Orange Book listings. This favors the patent holder, because he does not have to pay any damages for not modifying the Orange Book listing in time and there is apparently no time limit for making such modifications.

35. Hatch-Waxman Summary  Innovator gets:  Patent term extension/restoration  Guaranteed marketing exclusivity period  Automatic 30 month stay of FDA approval if litigation  Generic Gets:  Streamlined approval process  First-to-file 180-day marketing exclusivity  Safe harbor and possibility of definitive decision prior to launch A patent can be extended only once Patent must claim the active ingredient of the approved product One extension per regulatory review period Extension only applicable to the approved product, not all the claims of the patent

36. Conclusions :- Hatch-Waxman Amendments have been successful in encouraging generic entry. The 30-month stay and the 180-day marketing exclusivity provisions should be amended to ensure that the provisions are not gamed to delay or deter generic entry. The HWA provides an expedited USFDA drug approval program for speedy generic entry and Market Exclusivity as an incentive for continues innovation. Pre-HWA those seeking to market a generic version of a branded drug also had to carry out their own safety and efficacy studies much like the branded drug companies. Post-HWA for getting the generic approval the generic drug companies are not required to conduct the costly and time consuming clinical trials and tests. The generic drug companies are allowed to rely on the clinical studies done by the branded drug manufacturer. Unlike the pre-HWA era, undue patent extension may be avoided as the generic versions may be made available as soon as the patent term of the patented product is over.

37. Paragraph IV filings are generally associated with litigations as the patent owner tries to maintain its monopoly by bringing in picture the de facto preliminary injunction of 30 months by commencing an infringement suit against the generic drug manufacturer who applies for the generic version of the patented drug. The HWA also has provision for the generic drug manufacturer to invalidate the patent for branded drugs or at least prove that his generic version will not infringe the patent in question. The HWA also allows for a patent term extension of a maximum of 5 years for the branded drug manufacturer to compensate for the time lost during the NDA approval by the USFDA.

38. Authorized generics contravene the purposes of the Hatch-Waxman legislatively supervised, negotiated compromise. They “disrupt the ‘bounty’ system established by the Hatch-Waxman Act.’” The “loophole” in the Hatch-Waxman scheme that permits introduction of authorized generics during the 180-day exclusivity period, diverts a significant portion of sales that would be realized by a successful generic challenger to the authorized generic and its branded sponsor. Authorized generics negatively affect the incentive given to generic manufactures to challenge drug patents. Authorized generics may help consumers by lowering short-term prices. Authorized generics should “be banned as a strategic response to impending Paragraph IV entry, but should be allowed in their absence or after 180-day exclusivity expiration. The Hatch-Waxman Act should be amended to prohibit the introduction of an authorized generic equivalent to a branded product, either directly or indirectly, by an NDA holder, during the 180-day Hatch-Waxman exclusivity period. ADVANTAGES OF HATCH – WAXMAN ACT 1984

39. 1. en.wikipedia.org/wiki/Drug_Price_Competition_and_Patent_Term_Restoration_Acten.wikipedia.org/wiki/Drug_Price_Competition_and_Patent_Term_Restoration_Act 2. www.fda.gov/newsevents/testimony/ucm115033.htmwww.fda.gov/newsevents/testimony/ucm115033.htm 3.www.brinkshofer.com/resource_center/85-the-hatch-waxman-act-research-exempt-from- patent-infringementwww.brinkshofer.com/resource_center/85-the-hatch-waxman-act-research-exempt-from- patent-infringement