DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on May 4, 2026 has been entered.
Status of the Claims
Claims 1-28 were originally filed May 19, 2022.
The amendment received September 13, 2022 amended claims 1 and 15 and canceled claims 2, 3, 9-14, and 18-28.
The amendment received May 27, 2025 changed the status identifiers only.
The amendment received November 24, 2025 amended claims 1 and 4-6 and canceled claims 7 and 8.
The amendment received May 4, 2026 amended claims 1, canceled claims 4-6, and added new claims 29-32. Please note: claims 15 and 17 have improper status identifiers (i.e. should be “withdrawn”).
Claims 1, 15-17, and 29-32 are currently pending.
Claim 1 is currently under consideration.
Election/Restrictions
Applicant elected, without traverse, Group I (claims 1 and 4-8) in the reply filed on May 27, 2025.
Claims 15-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected method, there being no allowable generic or linking claim.
Applicant elected, without traverse, SEQ ID NO: 3 with I91L, R101A, Q123K, K207A, V343A, and R346V mutations; IgG1 Fc; and capable of inhibiting neutrophil elastase activity as the species in the reply filed on May 27, 2025. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 29-32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 27, 2025. Please note: new independent claim 32 is missing K207A.
Potential Rejoinder
Applicant elected claims directed to a product. If a product claim is subsequently found allowable, withdrawn process claims that depend from or otherwise include all the limitations of the allowable product claim will be rejoined in accordance with the provisions of MPEP § 821.04. Process claims that depend from or otherwise include all the limitations of the patentable product will be entered as a matter of right if the amendment is presented prior to final rejection or allowance, whichever is earlier. Amendments submitted after final rejection are governed by 37 CFR 1.116; amendments submitted after allowance are governed by 37 CFR 1.312.
In the event of rejoinder, the requirement for restriction between the product claims and the rejoined process claims will be withdrawn, and the rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to be allowable, the rejoined claims must meet all the criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103, and 112. Until an elected product claim is found allowable, an otherwise proper restriction requirement between product claims and process claims may be maintained. Withdrawn process claims that are not commensurate in scope with an allowed product claim will not be rejoined. See “Guidance on Treatment of Product and Process Claims in light of In re Ochiai, In re Brouwer and 35 U.S.C. § 103(b),” 1184 O.G. 86 (March 26, 1996). Additionally, in order to retain the right to rejoinder in accordance with the above policy, applicant is advised that the process claims should be amended during prosecution either to maintain dependency on the product claims or to otherwise include the limitations of the product claims. Failure to do so may result in a loss of the right to a rejoinder. Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the examiner before the patent issues. See MPEP § 804.01.
Sequence Interpretation
The Office interprets claims comprising SEQ ID NOs: in the following manner: “comprising a sequence of SEQ ID NO: 1” requires only a 2mer of SEQ ID NO: 1, “comprising the sequence of SEQ ID NO: 1” requires the full-length sequence with 100% identity to SEQ ID NO: 1 with any N-/C-terminal additions or any 5’/3’ additions, “consisting of SEQ ID NO: 1” requires the full-length sequence with 100% identity to SEQ ID NO: 1 and the same length as SEQ ID NO: 1, and “selected from the group consisting of SEQ ID NOs: 1, 2, and 3” requires the full-length sequence with 100% identity to SEQ ID NOs: 1, 2, or 3 and the same length as SEQ ID NOs: 1, 2, or 3.
Priority
The present application is a 371 (National Stage) of PCT/US2020/061347 filed November 19, 2020 which claims the benefit of 62/938,859 filed November 21, 2019.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Withdrawn Objections
The objection to claim 6 regarding “and” is missing between V343A, R346V (see line 5) is withdrawn in view of the amendment received May 4, 2026 which canceled the claim.
The objection to claim 6 regarding “in” in line 2 should be deleted is withdrawn in view of the amendment received May 4, 2026 which canceled the claim.
New Objections Necessitated by Amendment
Claim Objections
Claim 1 is objected to because of the following informalities: a conjunction is missing between “a)” and “b)”. Appropriate correction is required.
Claim 1 is objected to because of the following informalities: “and” in “b)” should read “and/or” to correlate with “one or more”. Appropriate correction is required.
Claim 1 is objected to because of the following informalities: “with” should be “to” (see line 7). Appropriate correction is required.
New Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 1 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. One of skill in the art would not be able to determine the scope of the present claims. For example, it is unclear how much of “SEQ ID NO: 3” is required (i.e. open, closed, etc.).
Claim 1 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. One of skill in the art would not be able to determine the scope of the present claims. For example, it is unclear how the Fc domain is attached (e.g. fusion polypeptide, covalent bond, noncovalent bond, intervening linker, etc.).
Withdrawn Rejections
The rejection of claim 1 under 35 U.S.C. 103 as being unpatentable over Lawrence et al. WO 97/39028 published October 23, 1997 and Wu et al., 2014, Pharmacokinetics of Peptide-Fc Fusion Proteins, Journal of Pharmaceutical Sciences, 103: 53-64 is withdrawn in view of the claims amendments received May 4, 2026.
The rejection of claims 1 and 4 under 35 U.S.C. 103 as being unpatentable over Li et al., 2013, Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1, PNAS, E4941-E4949 and Wu et al., 2014, Pharmacokinetics of Peptide-Fc Fusion Proteins, Journal of Pharmaceutical Sciences, 103: 53-64 is withdrawn in view of the claims amendments received May 4, 2026.
The rejection of claims 1 and 4 under 35 U.S.C. 103 as being unpatentable over Lawrence et al. WO 97/39028 published October 23, 1997; Wu et al., 2014, Pharmacokinetics of Peptide-Fc Fusion Proteins, Journal of Pharmaceutical Sciences, 103: 53-64; and Li et al., 2013, Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1, PNAS, E4941-E4949 is withdrawn in view of the claims amendments received May 4, 2026.
The rejection of claims 1, 5, and 6 under 35 U.S.C. 103 as being unpatentable over Xu et al., 2004, Conservation of Critical Functional Domains in Murine Plasminogen Activator Inhibitor-1, The Journal of Biological Chemistry, 279(17): 17914-17920 and Wu et al., 2014, Pharmacokinetics of Peptide-Fc Fusion Proteins, Journal of Pharmaceutical Sciences, 103: 53-64 is withdrawn in view of the claims amendments received May 4, 2026 is withdrawn in view of the claims amendments received May 4, 2026.
The rejection of claim 1 on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 7,388,074 in view of Wu et al., 2014, Pharmacokinetics of Peptide-Fc Fusion Proteins, Journal of Pharmaceutical Sciences, 103: 53-64 is withdrawn in view of the claims amendments received May 4, 2026.
The rejection of claim 1 on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 6,489,143 in view of Wu et al., 2014, Pharmacokinetics of Peptide-Fc Fusion Proteins, Journal of Pharmaceutical Sciences, 103: 53-64 is withdrawn in view of the claims amendments received May 4, 2026.
The rejection of claim 1 on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 6,103,498 in view of Wu et al., 2014, Pharmacokinetics of Peptide-Fc Fusion Proteins, Journal of Pharmaceutical Sciences, 103: 53-64 is withdrawn in view of the claims amendments received May 4, 2026.
Maintained and/or Modified* Rejections
*wherein the modification is due to amendment
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Lawrence et al. WO 97/39028 published October 23, 1997; Wu et al., 2014, Pharmacokinetics of Peptide-Fc Fusion Proteins, Journal of Pharmaceutical Sciences, 103: 53-64; Li et al., 2013, Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1, PNAS, E4941-E4949; and Xu et al., 2004, Conservation of Critical Functional Domains in Murine Plasminogen Activator Inhibitor-1, The Journal of Biological Chemistry, 279(17): 17914-17920.
For present claim 1, Lawrence et al. teach human PAI-1 mutants comprising I91L, Q123K, V343A, and/or R346V which inhibit neutrophil elastase activity and vitronectin binding (please refer to the entire specification particularly the abstract; Description; Figures; Examples; claims; pages 1, 2, 4-11, 13-15, 20, 22, 23, 24, 26, 30, 67-71, 89).
However, Lawrence et al. do not teach a Fc fusion.
For present claim 1, Wu et al. teach the benefits of conjugating Fc to polypeptides including extended half-life (please refer to the entire specification particularly the abstract; Introduction; Table 2; Distinct PK Characteristics of Peptibodies).
However, Lawrence et al. do not teach a K207A mutation.
For present claim 1, Li et al. teach human PAI-1 mutants comprising K176A, K207A, or K263A (please refer to the entire specification particularly the abstract; “Identification of the CDE-096 Binding Site”; Figures 5 and 6; “Inhibitory Mechanism Against Protease Binding”; “Inhibitory Mechanism Against Vitronectin Binding”).
However, Lawrence et al. do not teach a R101A mutation.
For present claim 1, Xu et al. teach PAI-1 mutants comprising Q123A and/or R101A and also R346A (please refer to the entire specification particularly the abstract; Figures 1-5). Please note: Xu et al. teaches both murine and human PAI-1. Mutation of conserved residues in different species (e.g. human) would be an obvious variation.
All the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in the respective functions and the combination would have yielded predictable results (i.e. addition of Fc extends serum half-life; various mutants of PAI-1 with known functions) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because a particular known technique (i.e. fusing Fc to polypeptides; PAI-1 mutagenesis) was recognized as part of the ordinary capabilities of one skilled in the art. The claims would have been obvious because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.” (e.g. making fusion polypeptides with Fc to extend serum half-life). See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Arguments and Response
Applicants’ arguments directed to the rejection under 35 USC 103 as being unpatentable over Lawrence et al.; Wu et al.; Li et al.; and Xu et al. for claim 1 were considered but are not persuasive for the following reasons.
Applicant contends that the prior art does not teach the required combination of mutations in new claim 32 (i.e. I91L, R101A, Q123K, V343A, and R346V with at least one of K69A, K80A, and K88A). Applicant contends that hindsight reasoning was utilized. Applicant contends that the prior art does not teach various functions (e.g. neutrophil elastase inhibitory activity, reducing vitronectin binding, reducing LRP1-mediated clearance, and benefiting from Fc-mediated pharmacokinetic improvement). Applicants contend that unexpected results are present (i.e. MDI-1003 with I91L, R101A, Q123K, V343A, and R346V – missing the required K207A mutation of independent claim 1).
Applicants’ arguments are not convincing since the teachings of Lawrence et al.; Wu et al.; Li et al.; and Xu et al. render the PAI-1 variant of the instant claims prima facie obvious.
Applicants elected the species of SEQ ID NO: 3 with I91L, R101A, Q123K, K207A, V343A, and R346V mutations in the reply filed on May 27, 2025 (i.e. mutations at any of residues K69A, K80A, and K88A were not elected). Therefore, present new claim 32 is withdrawn from prosecution as being drawn to a nonelected species (see the Election/Restrictions section above). New independent claim 32 is missing K207A and also includes additional nonelected mutations.
During the interview of April 28, 2026 and as discussed in the Interview summary mailed on April 30, 2026, it was stated that as long at the INDEPENDENT claim (i.e. independent claim 1) was amended with additional REQUIRED species (i.e. not the optional species of independent claim 1 or the introduction of a new independent claim), the additional species may be examined to advance prosecution (e.g. election by original presentation would not be invoked). This was for an RCE only. If applicants amend the independent claim 1 with additional species in response to the present Office Action, election by original presentation will be invoked.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Lawrence et al. teach human PAI-1 mutants comprising I91L, Q123K, V343A, and/or R346V which inhibit neutrophil elastase activity, vitronectin binding, and alter LRP1-mediated clearance (please refer to the entire specification particularly the abstract; Description, Figures, Examples, claims).
Xu et al. teach that PAI-1 mutants (i.e. Q123K, R101A, or both) can decrease vitronectin binding (please refer to the entire reference particularly Figure 3) and alter LRP binding (please refer to the entire reference particularly Figure 5).
Li et al. teach that PAI-1 mutants can inhibit protease binding and vitronectin binding (please refer to the entire reference particularly “Inhibitory Mechanism Against Protease Binding”, “Inhibitory Mechanism Against Vitronectin Binding”).
Utilizing Fc fused to various polypeptides is well-known in the art to improve pharmacokinetic improvement. Wu et al. teach the benefits of conjugating Fc to polypeptides including extended half-life (please refer to the entire specification particularly the abstract; Introduction; Table 2; Distinct PK Characteristics of Peptibodies). See also Jafari et al., 2017, Fc-fusion Proteins in Therapy: An Updated View, Current Medicinal Chemistry, 24: 1228-1237.
Page 47 of the originally filed specification describes MDI-1001, MDI-1002, MDI-1003, and MDI-1004.
MDI-1001 is SEQ ID NO: 3 (human PAI-1) with I91L, V343A (neutrophil elastase inhibitory activity), and R346V (neutrophil elastase inhibitory activity).
MDI-1002 is MDI-1001-Fc
MDI-1003 is MDI-1001 further comprising R101A (reducing vitronectin binding) and Q123K (reducing vitronectin binding)
MDI-1004 is MDI-1003-Fc
Unexpected results MUST be commensurate in scope with the present claims. MDI-1003 does not require a K207A mutation.
Furthermore, the results are not unexpected.
Lawrence et al. teach human PAI-1 mutants comprising I91L, Q123K, V343A, and/or R346V which inhibit neutrophil elastase activity, vitronectin binding, and alter LRP1-mediated clearance (please refer to the entire specification particularly the abstract; Description, Figures, Examples, claims).
Xu et al. teach that PAI-1 mutants (i.e. Q123K, R101A, or both) can decrease vitronectin binding (please refer to the entire reference particularly Figure 3) and alter LRP binding (please refer to the entire reference particularly Figure 5).
Simply because the exact same experiments were not performed (i.e. lung fibrosis, recovery after bleomycin-induced lung injury, etc.) in the prior art does not mean that the results are unexpected. The prior art teaches the same activity is associated with the presently claimed mutations (see above).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 7,388,074 in view of Wu et al., 2014, Pharmacokinetics of Peptide-Fc Fusion Proteins, Journal of Pharmaceutical Sciences, 103: 53-64; Li et al., 2013, Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1, PNAS, E4941-E4949; and Xu et al., 2004, Conservation of Critical Functional Domains in Murine Plasminogen Activator Inhibitor-1, The Journal of Biological Chemistry, 279(17): 17914-17920.
U.S. Patent No. 7,388,074 claims PAI-1 with I91L, V343A, and/or R346V mutations.
Wu et al. teach the benefits of conjugating Fc to polypeptides including extended half-life (please refer to the entire specification particularly the abstract; Introduction; Table 2; Distinct PK Characteristics of Peptibodies).
Li et al. teach human PAI-1 mutants comprising K176A, K207A, or K263A (please refer to the entire specification particularly the abstract; “Identification of the CDE-096 Binding Site”; Figures 5 and 6; “Inhibitory Mechanism Against Protease Binding”; “Inhibitory Mechanism Against Vitronectin Binding”).
Xu et al. teach PAI-1 mutants comprising Q123A and/or R101A (please refer to the entire specification particularly the abstract; Figures 1-5).
All the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in the respective functions and the combination would have yielded predictable results (i.e. addition of Fc extends serum half-life; various mutants of PAI-1 with known functions) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because a particular known technique (i.e. fusing Fc to polypeptides; PAI-1 mutagenesis) was recognized as part of the ordinary capabilities of one skilled in the art. The claims would have been obvious because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.” (e.g. making fusion polypeptides with Fc to extend serum half-life). See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Arguments and Response
Applicants’ arguments directed to the rejection on the ground of nonstatutory obviousness-type double patenting as being unpatentable over U.S. Patent No. 7,388,074 in view of Wu et al.; Li et al.; and Xu et al. for claim 1 were considered but are not persuasive for the following reasons.
Applicant contend that the same arguments regarding the 35 USC 103 rejections are pertinent to the present rejection.
Applicants’ arguments are not convincing since the claimed invention of U.S. Patent No. 7,388,074 in view of Wu et al.; Li et al.; and Xu et al. renders obvious the PAI-1 variant of the instant claims. In addition, while a request may be made that objections or requirements as to form not necessary to further consideration of the claims be held in abeyance until allowable subject matter is indicated, the present is a rejection and will not be held in abeyance (see MPEP § 714.02). The arguments for the 35 USC 103 rejection above are incorporated herein.
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 6,489,143 in view of Wu et al., 2014, Pharmacokinetics of Peptide-Fc Fusion Proteins, Journal of Pharmaceutical Sciences, 103: 53-64; Li et al., 2013, Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1, PNAS, E4941-E4949; and Xu et al., 2004, Conservation of Critical Functional Domains in Murine Plasminogen Activator Inhibitor-1, The Journal of Biological Chemistry, 279(17): 17914-17920.
U.S. Patent No. 6,489,143 claims PAI-1 with I91L, V343A, and/or R346V mutations (please note the method claims to produce the protein from the claimed nucleic acids).
Wu et al. teach the benefits of conjugating Fc to polypeptides including extended half-life (please refer to the entire specification particularly the abstract; Introduction; Table 2; Distinct PK Characteristics of Peptibodies).
Li et al. teach human PAI-1 mutants comprising K176A, K207A, or K263A (please refer to the entire specification particularly the abstract; “Identification of the CDE-096 Binding Site”; Figures 5 and 6; “Inhibitory Mechanism Against Protease Binding”; “Inhibitory Mechanism Against Vitronectin Binding”).
Xu et al. teach PAI-1 mutants comprising Q123A and/or R101A (please refer to the entire specification particularly the abstract; Figures 1-5).
All the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in the respective functions and the combination would have yielded predictable results (i.e. addition of Fc extends serum half-life; various mutants of PAI-1 with known functions) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because a particular known technique (i.e. fusing Fc to polypeptides; PAI-1 mutagenesis) was recognized as part of the ordinary capabilities of one skilled in the art. The claims would have been obvious because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.” (e.g. making fusion polypeptides with Fc to extend serum half-life). See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Arguments and Response
Applicants’ arguments directed to the rejection on the ground of nonstatutory obviousness-type double patenting as being unpatentable over 1-15 of U.S. Patent No. 6,489,143 in view of Wu et al.; Li et al.; and Xu et al. for claim 1 were considered but are not persuasive for the following reasons.
Applicant contend that the same arguments regarding the 35 USC 103 rejections are pertinent to the present rejection.
Applicants’ arguments are not convincing since the claimed invention of U.S. Patent No. 6,489,143 in view of Wu et al.; Li et al.; and Xu et al. renders obvious the PAI-1 variant of the instant claims. In addition, while a request may be made that objections or requirements as to form not necessary to further consideration of the claims be held in abeyance until allowable subject matter is indicated, the present is a rejection and will not be held in abeyance (see MPEP § 714.02). The arguments for the 35 USC 103 rejection above are incorporated herein.
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 6,103,498 in view of Wu et al., 2014, Pharmacokinetics of Peptide-Fc Fusion Proteins, Journal of Pharmaceutical Sciences, 103: 53-64; Li et al., 2013, Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1, PNAS, E4941-E4949; and Xu et al., 2004, Conservation of Critical Functional Domains in Murine Plasminogen Activator Inhibitor-1, The Journal of Biological Chemistry, 279(17): 17914-17920.
U.S. Patent No. 6,103,498 claims PAI-1 with I91L, V343A, and/or R346V mutations.
Wu et al. teach the benefits of conjugating Fc to polypeptides including extended half-life (please refer to the entire specification particularly the abstract; Introduction; Table 2; Distinct PK Characteristics of Peptibodies).
Li et al. teach human PAI-1 mutants comprising K176A, K207A, or K263A (please refer to the entire specification particularly the abstract; “Identification of the CDE-096 Binding Site”; Figures 5 and 6; “Inhibitory Mechanism Against Protease Binding”; “Inhibitory Mechanism Against Vitronectin Binding”).
Xu et al. teach PAI-1 mutants comprising Q123A and/or R101A (please refer to the entire specification particularly the abstract; Figures 1-5).
All the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in the respective functions and the combination would have yielded predictable results (i.e. addition of Fc extends serum half-life; various mutants of PAI-1 with known functions) to one of ordinary skill in the art at the time of the invention. The claims would have been obvious because a particular known technique (i.e. fusing Fc to polypeptides; PAI-1 mutagenesis) was recognized as part of the ordinary capabilities of one skilled in the art. The claims would have been obvious because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.” (e.g. making fusion polypeptides with Fc to extend serum half-life). See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
Arguments and Response
Applicants’ arguments directed to the rejection on the ground of nonstatutory obviousness-type double patenting as being unpatentable over U.S. Patent No. 6,103,498 in view of Wu et al.; Li et al.; and Xu et al. for claim 1 were considered but are not persuasive for the following reasons.
Applicant contend that the same arguments regarding the 35 USC 103 rejections are pertinent to the present rejection.
Applicants’ arguments are not convincing since the claimed invention of U.S. Patent No. 6,103,498 in view of Wu et al.; Li et al.; and Xu et al. renders obvious the PAI-1 variant of the instant claims. In addition, while a request may be made that objections or requirements as to form not necessary to further consideration of the claims be held in abeyance until allowable subject matter is indicated, the present is a rejection and will not be held in abeyance (see MPEP § 714.02). The arguments for the 35 USC 103 rejection above are incorporated herein.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Jafari et al., 2017, Fc-fusion Proteins in Therapy: An Updated View, Current Medicinal Chemistry, 24: 1228-1237.
U.S. Patent Application Publications 2010/0137194 (see paragraph 555) and 2010/0286053 (see paragraph 79) both teach PAI-1 mutants comprising R101A and Q123K.
Regarding mutations K69A, K80A, and K88A, please refer to Horn et al., 1998, Plasminogen activator inhibitor 1 contains a cryptic high affinity receptor binding site that is exposed upon complex formation with tissue-type plasminogen activator, Thromb Haemost, 80(5): 822-828.
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/AMBER D STEELE/Primary Examiner, Art Unit 1658
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