Biopharmaceutical Intellectual Property – Case Studies

1. Hsiu-Ming Saunders, Ph.D, J.D. Attorney at Law U.S. Tel: (650) 557-4464 mingsaun@gmail.com November 2008 Biopharmaceutical Intellectual Property – Case Studies

2. Table of Contents • Content of U.S. Patent Applications • Patent Strategy • Practical Considerations for Patent Portfolio Development • Overcoming Examiner Rejections – Real cases • Problems encountered by Asian inventors in Applying for U.S. Patent Applications

3. Contents of U.S. Patent Application • Title of the Invention • Background of the Invention • Field of the Invention • Summary of the Invention • Brief Description of Drawings • Detailed Description of the Invention • Claims • Abstract • Drawings

4. Two Prongs of Patent Strategy • Defensive Use • Patent Portfolio Building - create value for the company

5. PatentPortfolio Philosophy • Obtain strong, enforceable patents • Build the highest quality patent portfolio

6. Obtaining Valuable Patents • Pioneer technology or major improvement • Invention creates new industry • Invention is so new • Roadblocks • competitors must infringe patent to carry out their enterprises • Widespread applications • across many different industries • Easy to Detect Infringement • claims that are easy to read on competitors’ device or process

7. Practical Considerations of Patent Portfolio Development • Disclosure – must fully disclose the invention to the public in return for monopoly (is trade secret protection more effective?) • Cost – patents can be expensive to procure and maintain and are even expensive to enforce • Time – inventors and others in company must invest time in process to obtain and enforce patents • Process – patents generally require 2 - 4 years to obtain • Possible Loss of Patent Rights – company must monitor sales efforts, publications, or other events that might result in loss of patent rights

8. Overcoming Examiner’s Rejections – Real case illustrations • Restriction Requirement • Obviousness Rejection • Enablement Rejection • Written Description Rejection

9. Restriction Requirement • What is it? (group election, species election) • Examiner’s position • Applicant’s position • Patent Attorney’s position • Response: • Elect • without traverse • with traverse

10. Restriction Requirement: Real Case illustration # 1 U.S. Application No. 10/893,551 Title: “Compositions of Protein Mimetics and Methods of Using Same Against HIV-1, Sars-Cov and the Like” Claim: A protein mimetic for preventing HIV entry into a host cell comprising: a. at lest two peptide strands, and b. an interstrand linker coupling the peptide strands

11. Peptide strand: T1249 WMEWYTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF C34 WMEWDREINNYTSLIHSLIEESQNQQEKNEQELL DP178 YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF

12. Interstrand linker structure I

13. Interstrand linker structure II

14. Restriction Requirement from the Examiner: “[r]estriction to one of the following inventions is required . . . : I. Claims 1-15, 23-29, 30-37 and 45-51 are drawn to a protein mimetic comprised of two peptides covalently linked together and capable of inhibiting fusion of two separate membranes, classified in class 530, subclass 332. II. Claims 16-22 and 38-44, drawn to a method for preventing or treating HIV-1 using the pharmacological composition of Group I, classified in class 514, subclass 2.”

15. Restriction Requirement The Examiner also stated that: “[n]o matter which group is elected, a further election of species is required. This application contains claims directed to the following patentably distinct species: Various peptidomimetics (see for example claims 3-5).”

16. Arguments: These peptide strands are not patentably distinct species T1249 WMEWYTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF C34 WMEWDREINNYTSLIHSLIEESQNQQEKNEQELL DP178 YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF • Contain the same amino acid fragment 638-662; and • DP178 is a partial fragment of T1249

17. Arguments: Interstrand linkers of Formula I and II are not patentably distinct because They belong to the same genus of the compound of the formula depicted below: Formula III

18. Successful Outcome • The arguments overcame the species election requirement. “Applicant’s election with traverse of invention I . . . is acknowledged. The traversal is on the ground(s) that peptide T1249 and C34 are not patentably distinct from the elected peptide DP179; linker I and II are not patentably distinct. This is found persuasive because of applicants’ arguments.”

19. The cost of wrong election • not unusual: It happens. • serious outcomes: • Wrong prosecution direction; • End up abandoning the pending case.

20. What is the cause of wrong election? 1. Wrong claims: • not claiming essence of the invention  resulting in wrong grouping and wrong election 2. Simply electing a legally wrong group

21. What can you do if a wrong election has been made? How to fix it? • case by case: • Amending claims, arguments/remarks with legal support--costly • RCE—more costly • Filing a new continuation application— the most costly

22. Take home message: • Do it right at the early stage to avoid restriction requirements, wrong groupings, wrong elections

23. Overcoming Rejections under Enablement, written description, obviousness U.S. Application No. 10/999,393 (Case #2) “Anti-Thrombotic Thrombin Variants” Invention: (claim 1 as illustration) 1. A variant thrombin comprising an amino acid sequence having the substitutions W215A and E217A, wherein the amino acid sequence is at least 80% identical to the sequence set forth in SEQ ID NO: 3.

24. In Office Action Feb. 21, 2006, Examiner rejected all claims • Enablement Rejection • while being enabling for the thrombin variant of SEQ ID NO:3, does not reasonably provide enablement for a thrombin variant that has substitutions W215 and E217 and is at least 80% identical to SEQ ID NO:3. • Written Description Rejection • The specification does not contain any disclosure of the function of all said polypeptides. • Obviousness Rejection • rejected as being unpatentable over Gibbs et al., 1995 in view of Arosio et al., 2000 (IDS) or Ayala et al., 2001. • Examiner asserted: suggestion and motivation to combine is based on skilled artisan’s desire to provide a thrombin variant with enhanced protein C activity and decreased fibrinogen cleavage.

25. Argued in June 20, 2006 Response: • Enablement One of ordinary skilled in the art could practice the invention without undue experimentation (1) Nature of the invention (2) Breadth of claims (3) Guidance (4) Working Examples (5) Quantity of experimentation necessary (6) Relative skill of those in the art

26. Argued in June 20, 2006 Response Insufficient Written Description: The working examples disclosed in the specification are representative to the function of the claimed thrombin variants. Further, the specification has detail descriptions of making and testing WE thrombin variants. Thus, Applicants had contemplated and possessed the claimed invention at the time when the application was filed.

27. Argued in June 20, 2006 Response Obviousness • Neither reference provides any suggestion or motivation for making a thrombin variant that has two substitutions, let alone two substitutions W215A and E217A. • Claimed invention is non-obvious because of the unexpected properties. • The combination product WE has an synergy effect on reducing the release of fibrinopeptides A and B. See Tables 1 and 2 • (Fibrinogen: E217A: W215A:WE = 0.27:0.034:0.00089; Fibrin: E217A: W215A:WE = 0.15:0.053:0.0021) • Contrary to the examiner’s assertion, the combination of E217 and W215A produces a dramatically decreased, rather than enhanced, protein C activity. See Table 2 data for Protein C + TM (E217A:W215A:WE = 140:75:33).

28. Final Office Action Aug. 24, 2006: Examiner maintained rejections • Enablement • “determining which of all polypeptides having at least 80% homology to SEQ ID NO: 3have the desired activity would require undue experimentation.” • Insufficient written description • Claim 1 fails to provide any functional limitations for the recited thrombin variants. Therefore, the polypeptides encompassed by the recited genus have any or no activity.

29. In Final Office Action Aug. 24, 2006, Examiner maintained rejections • Obviousness • The “synergistic effect is not unexpected” and that “many enzymes have allosteric sites that act synergistically in both the activation and inhibition of the enzyme.” Citing Metzler et al (2001). • “The skilled artisan would know that it is the ratio of protein C activity to fibrinogen clotting activity (PA/FC), not the absolute protein C activity, that determines whether the action of thrombin will be primarily anti-coagulation, via the activation of protein C, or procoagulation, via cleavage of thrombin*.” (*: fibrinogen)

30. Response to the Final Office Action: Vigorously Refuted Examiner’s points • Enablement and written description: • Amended claim 1 to require the variant thrombin W215A/E217A having the amino acid sequence set forth in SEQ ID No: 3 • Obviousness: • The invention E217A/W215A possesses unexpected synergistic properties as shown in the attached Exhibit A. • addressed and Refuted Examiner’s each point by citing scientific authority

31. Exhibit AThe invention Shows Synergistic Results (From Tables 1 and 2, see Specification, pages 48 and 50)

32. Comparative Data Between Cited References and the Invention (Exhibit A continued) *PA/FC here are calculated from the data shown in Tables 1 and 2. The term "PA/FC ratio" as used herein refers to the ratio of the percent of wild-type protein C activation (PA) activity remaining in a thrombin variant relative to the percent of wild-type fibrinogen clotting (FC) activity remaining in the thrombin variant. A value of PA/FC greater than 1.0 indicates that the thrombin variant has reduced procoagulant fibrinogen cleavage activity relative to the residual anticoagulant activity resulting from protein C activation.

33. Response to the Final Office Action: Vigorously Refuted Examiner’s points • The life science/Biotechnology being in the area of unpredictable art, a synergistic effect cannot reasonably or necessarily be expected from allosteric sites. • McLennan reported that Hemoglobin has three allosteric sites, and their interactions are non-synergistic but are simply additive. See attached Abstract (Biochemistry and Molecular Biology International, Vol. 44, No. 1, pages 175-183, 1998). • Rao G.S. reported that Ascaris suumphosphofructokinase has two allosteric sites, one for fructose 2,6-biphosphate and one for AMP, and that their effects on the enzyme are additive and not synergistic. See attached Abstract (Archives of Biochemistry and Biophysics, Vol. 365, No. 2, pages 335-343(9), 1999.)

34. Vigorously Refuted Examiner’s points in Response to the Final Office Action • Examiner shifted the basis of motivation after Applicants had responded by pointing out that the combination of E217A and W215A produced a decreased, rather than enhanced protein C activity. • if the motivation to combine the two references were really that obvious as the Examiner alleged, the Examiner would have asserted the motivation based on the skilled artisan's desire to provide an enhanced PC/PF ratio at the first place, rather than alleged “the skilled artisan's desire to provide a thrombin variant with enhanced protein C activation.

35. Successful Outcome • Enablement and written description rejection were withdrawn for the following reasons. “The means by which the function of thrombin is regulated by its structure has been well characterized (Tsiang et al, 1995; Richardson et al, 2000). Therefore, it would not be undue experimentatikon for the skilled artisan to make and use the full scope of the recited thrombin variants; Applicants were in possession of their recited invention.”

36. Successful Outcome • Overcame obviousness rejection • “The extent of synergy resulting from the double W215A+E217A mutation is far greater than expected. As disclosed by Applicant’s analysis in Exhibit A, filed Jan. 18, 2007, the single mutation E217A gives a PA/FC of 19.1 (Gibbs et al; Table 1), the single mutation W215A gives a PA/FC of 170 (Arosio et al; Table 1), while Applicants’ W215A_E217A thrombin variant has a PA/FC of 2865. Such dramatic synergy is far greater than expected and, as such, the unexpected results overcome the prior obviousness rejection (MPEP 716.02(c)). For these reasons, rejections of Claims 1, 2, 6, 7, 16-18, 44 and 45 under 35 USC 103(a). . . is withdrawn.

37. Successful Outcome Patent granted and issued May 29, 2007 U.S. 7,223,583 “Antithrombotic thrombin variants” Claim 1. A protein comprising a variant thrombin, wherein the variant thrombin is at least 80% identical to the sequence set forth by SEQ ID NO: 3 and comprises the residues corresponding to Ala263 and Ala265 of SEQ ID NO: 3, and wherein the variant thrombin has a PA/FC ratio greater than 1.0.

38. Case #3 • U.S. 10/310,002 “Insulin-Responsive DNA Binding Protein-1 And Methods To Regulate Insulin- Responsive Genes” • Filling date: 12/04/2002

39. Case #3: U.S. 10/310,002 • Discovering a new gene encoding a transcription factor that is responsive to Insulin (cDNA clones from mouse, and human) • Data • Cell culture studies: Cells treansfected with the gene show a increase in glucose uptake; parallel studies with insulin, and a Thiazolidinedione compound • Transgenic mice studies: introducing the gene into the diabetes mouse model showed a decrease in serum glucose

40. Case #3: U.S. 10/310,002 • Original filed Claims: 86 • Problems: • excess of claims - cost - Restriction requirement

41. U.S. 10/310,002: Restriction Requirement 7 Groups: 1. Isolated nucleic acids 2. A polypeptide 3. An antibody 4. A method of regulating expression of nucleic acid encoding an IRDBP-1 polypeptide 5. A method of regulating serum glucose in an animal (5 claims) 6. A method of detecting a nucleic acid encoding an IRDBP-1 polypeptide 7. A method of detecting an IRDBP-1 polypeptide

42. U.S. 10/310,002: Restriction Requirement • Elected Group 3: A method of regulating serum glucose in an animal • 86  5 claims • Waste of fees

43. U.S. 10/310,002: Restriction Requirement Elected Claims: 65. A method of regulating a serum glucose level in an animal or human, comprising the steps of: (a) administering to an animal or human an effective amount of a pharmaceutically acceptable composition comprising a compound capable of modulating the activity of IRDBP-1; and (b) modulating the activity of IRDBP-1, thereby regulating the serum glucose level in the animal or human.

44. U.S. 10/310,002: Restriction Requirement First Office Action on merit: 3/18/2005 §112, first paragraph, enablement and written description §102: prior art teaching Thiazolidinedione compounds

45. Amended Claim: 65. A method of regulating a serum glucose level in an animal or human, comprising the steps of: modulating the metabolic activity of IRDBP-1in the animal or human to increase the phosphorylation of IRDBP-1, thereby increasing glucose transport into a cell of the animal or human, wherein when the glucose transport into a cell of the animal or human increases, the serum glucose level in the animal or human decreases accordingly. Questions: Why is the step (a) deleted? - Is the wherein clause necessary here? - Does this claim include all essential steps?

46. U.S. 10/310,002 Final Rejection: 11/10/2005 • Maintained §102: prior art teaching Thiazolidinedione compounds • New ground rejection: §101, non-statutory subject matter (naturally occurring process) • §112: first paragraph (b/c modulating the metabolic activity of IRDBP-1) • §102: prior art (Guyton’s Textbook of Medical Physiology “Insulin, glucagon and diabetes mellitus”)

47. U.S. 10/310,002: File RCE/Amendments 65. A method of regulating a serum glucose level in an animal or human with diabetes mellitus and/or insulin resistance, comprising the steps of: modulating the activity of IRDBP-1 by increasing at least one of the intracellular level, DNA binding activity, gene transcriptional activity, proteolytic cleavage, nuclear entry, and phosphorylation of IRDBP-1, thereby increasing glucose transport into a cell of the animal or human, wherein when the glucose transport into a cell of the animal or human increases, the serum glucose level in the animal or human decreases accordingly. • Question: Are the above amendments making any sense?

48. U.S. 10/310,002: File RCE RCE, First Office Action Final 03/02/2006 • §101, non-statutory subject matter (naturally occurring process) • Maintained §102: prior art teaching Thiazolidinedione compounds

49. U.S. 10/310,002:2nd RCE/My Amendments 65. A method of regulating a serum glucose level in an animal or human with diabetes mellitus and/or insulin resistance, comprising the steps of: • increasing an intracellular IRDBP-1 level, thereby increasing glucose transport into a cell of the animal or human and decreasing the serum glucose level in the animal or human, wherein the step of increasing the intracellular IRDBP-1 level is insulin-independent.

50. U.S. 10/310,002:2nd RCE/My Amendments 2nd RCE, First Office Action 10/20/2006 • Withdraw §101, non-statutory subject matter (naturally occurring process) • Withdraw §102: prior art teaching Thiazolidinedione compounds • §112 enablement and written description : (directed to administering any compound capable of increasing an intracellular IRDBP-1 level in a cell of the animal . . . )