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 .
Claims 1-4, 6-7, and 19 have been cancelled.
Applicant's arguments filed 7/1/2025 have been fully considered but they are not fully persuasive.
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 7/5/2023 is again acknowledged.
Claims 10-18 and 22-25 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/5/2023.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 5, 8-9, and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Thallapuranam et al. (U.S. Patent Application Publication 2017/0281790) or Thallapuranam et al. (U.S Patent No. 10,385,113, of record) in view of Bogin et al. (U.S. Patent No. 7,563,769), and Evans et al. (U.S. Patent Application Publication 2018/0319857).
Instant SEQ ID NO: 4 is 155 amino acids and has the mutations Q65L, N111S, K128N, and K138E.
Thallapuranam et al. (U.S. Patent Application Publication 2017/0281790) is the published application of Thallapuranam et al. (U.S Patent No. 10,385,113, of record). They are equivalent documents. The published application will be pointed to.
Thallapuranam et al. discloses engineered FGF-2 compositions. Figure 14 discloses FGF-2 mutant SEQ ID NO: 10 having a K138E mutation. Variants having 90-99% sequence identity to SEQ ID NOS: 10 are disclosed. 98% or more sequence identity is specifically disclosed. See at least paragraphs [0038-0042]. Fusion proteins including membrane permeable peptides are disclosed. See at least paragraph [0043]. Pharmaceutical compositions including hydrogels are disclosed. See at least paragraph [0055]. The base sequence for the 155 amino acid form of FGF-2 is SEQ ID NO: 8. Thallapuranam et al. does not disclose an FGF-2 mutant corresponding to instant SEQ ID NO: 4.
Bogin discloses FGF-2 mutant proteins having N111 mutations. SEQ ID NO: 1 is the 155 amino acid form of FGF-2 (corresponding to instant SEQ ID NO: 3) and has a wild-card Xaa at amino acid position 111 and indicates that this amino acid position can be anything other than N. Claim 1 indicates that amino acid position 111 can be serine (i.e. N111S). Claim 9 is directed to pharmaceutical compositions. Substitution at position N111 provides receptor specificity. See at least column 5, lines 22-26.
Evans et al. discloses FGF-2 mutants having combinations of mutations. An FGF2 protein comprising a mutation at one or more of G19, H25, F26, K30, Y33, R53, Q65, S73, C96, E105, N111, Y112, N113, R116, S117, R118, K119, Y120, T121, S122, W123, K128, R129, Q132, K134, and S137, in SEQ ID NO: 3 (the 155 amino acid form) is disclosed and claimed. Q65, N111, K128 are recited in instant claim 11. The mutations Q65L and K128N are specifically disclosed. At least for example, SEQ ID NO: 16 has K128N. Mutation at 1, 2, 3, or 4 of the recited positions is disclosed. See at least claims 11-12, Table 1, and paragraphs [0137-138]. Pharmaceutical compositions, including hydrogels, are disclosed. See at least paragraphs [0190-0197].
It would have been obvious to take the base sequence for the 155 amino acid form of FGF-2 as disclosed by Thallapuranam et al. and make the mutations Q65L (as taught by Evans et al.), N111S (as taught by Bogin et al., where mutation at this position is also taught by Evans et al.), K128N (as taught by Evans et al.), and K138E (as taught by Thallapuranam et al.) resulting in the polypeptide of instant SEQ ID NO: 4 and instant claim 8. Each of the individual mutations would have been known and the prior art to Thallapuranam et al. and Evans et al. specifically suggest combining known mutations. All of the various combinations would have been obvious as each of the individual mutations would have been known and the prior art specifically suggests combining known mutations. In particular, Thallapuranam et al. discloses sequence variation of 50-99% sequence identity, permitting extensive sequence variability within FGF-2 mutant polypeptides. A fusion protein according to instant claim 9 containing instant SEQ ID NO: 4 (a mutant FGF-2 suggested by the prior art), pharmaceutical compositions containing instant SEQ ID NO: 4 (a mutant FGF-2 suggested by the prior art), and hydrogels containing instant SEQ ID NO: 4 (a mutant FGF-2 suggested by the prior art) according to instant claim 21 would have been obvious in view of the disclosure of Thallapuranam et al.
Applicant’s arguments are not persuasive. The prior art fairly suggests combining known mutations in FGF-2. Applicant argues that superior results are achieved by introducing mutations at each of the four amino acid positions as recited in claim 5. However, applicant has asserted superior results for the mutated FGF-2 of SEQ ID NO: 4 (see claim 8) and any other FGF-2 within the scope of the claims (see claim 5 and at least 98% sequence identity limitation) without providing evidence establishing unexpected results. See at least MPEP 716.02(c).
Applicant submitted the Thallapuranam Declaration under 37 CFR 1.132 on 7/1/2025. This declaration has been considered but it does not establish unexpected results due to deficiencies in the evidence presented. First of all, Figure 3 labels the results as being for the double mutant K128N, K130E; that is, it appears to misidentify the mutations tested. In addition, the line in the figure corresponding to wild-type FGF2 and the line corresponding to FGF2 DM are not clearly identified. The declaration provides results for FGF2 modified with only two of the four required mutations. This double mutant is compared to wild-type FGF2; however, wild-type FGF2 is not the closest prior art. Unexpected results must be established with respect to the closest prior art. Thallapuranam et al. (U.S. Patent Application Publication 2017/0281790) and Thallapuranam et al. (U.S Patent No. 10,385,113) disclose FGF2 with the K138E mutation. Evans et al. discloses FGF2 with the K128N mutation and FGF2 with the Q65L mutation. Bogin et al. discloses FGF2 with the N111S mutation. These FGF2 mutants are the closer prior art then wild-type FGF2. It appears that the results for the FGF2 double mutant K128N/K138E in the Thallapuranam Declaration should have been compared to either or both of the FGF2 K128N single mutant or the FGF2 K138E single mutant. In addition, Chen et al. (U.S. Patent Application Publication. 2013/0236959, of record) documents that FGF2 having the K128N mutation would have been known to have increased thermostability as compared to wild-type FGF2. See at least abstract; Figures 7A-B; Figure 8; Figures 9A-C; Figure 10; and paragraphs [0034-0037 and 0081]. Increased thermostability for the mutant of instant SEQ ID NO: 4 (a mutant FGF-2 suggested by the prior art) would not have been unexpected. It is noted that thermostability in the Thallapuranam Declaration was evaluated by differential scanning calorimetry (DSC). This differs from how thermostability was determined in Chen et al. and differs from how thermostability was determined in the instant specification. The instant specification determined melting temperature by means of a plot of temperature versus fraction unfolded where a ratio of relative fluorescence intensity at 308 nm and 350 nm were used to calculate the fraction unfolded. See at least Figure 9 and page 4, lines 26-30. That is, the evidence presented in the Thallapuranam cannot be directly compared to that the results of Chen et al. or the results of the instant specification because the values were determined by different methods. It is also noted that the Thallapuranam Declaration does not indicate whether testing in Figure 3 was performed in the presence or absence of heparin. It appears it may have been in the absence of heparin based on the values in Table 1 of the instant specification that were being compared.
The declaration statements of belief concerning superior results or unexpected results must be supported by evidence. This evidence must be in the form of a comparison to the closest prior art and not wild-type FGF2. The comparison must be between data obtained in the same manner. That is, the melting temperature thermostability must be quantitated in the same manner so that the results can be directly compared.
Applicant is again reminded that any evidence of unexpected results must be commensurate in scope to the claims. See at least MPEP 716.02(d). Other mutations permitted by the 98% sequence identity in claim 5 are unspecified and could change the properties of the mutant FGF-2.
No unexpected results have been established.
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.
Claims 5, 8-9, and 20-21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, and 13-20 of U.S. Patent No. 10,385,113 (of record) in view of any of Bogin et al. (U.S. Patent No. 7,563,769) and Evans et al. (U.S. Patent Application Publication 2018/0319857).
Bogin et al. and Evans et al. are applied as above. None of the references discloses the mutation K138E as in instant claim 5, the polypeptide of instant SEQ ID NO: 4 in instant claim 8, or a fusion protein as in instant claim 9. Bogin et al. does not disclose hydrogels as in instant claim 21.
Issued claims 1, 13, and 17 are directed to FGF polypeptides having 80% sequence identity to SEQ ID NO: 10. The FGF-2 mutant SEQ ID NO: 10 is 155 amino acids and has the mutation K138E. Issued claim 4 is directed to a fusion protein comprising the FGF polypeptide of claim 1 and a membrane permeable peptide. Issued claims 5, 15, and 19 are directed to a pharmaceutical composition comprising the FGF polypeptide of claims 1, 13, and 17, respectively, and a pharmaceutical carrier. Issued claims 6, 16, and 20 are directed to a hydrogel comprising the FGF polypeptide of claims 1, 13, and 17, respectively.
Instant SEQ ID NO: 4 is 155 amino acids and has the mutations Q65L, N111S, K128N, and K138E.
It would have been obvious to take SEQ ID NO: 10 in the ‘113 claims as the 155 amino acid base sequence of FGF-2 and make the mutations Q65L (taught by Evans et al.), N111S (taught by Bogin et al.), and K128N (taught by Evans et al.) resulting in the polypeptide of instant SEQ ID NO: 4 and instant claim 8. The K138E mutation is in the issued claims. Each of the individual mutations would have been known and the prior art to Evans et al. specifically suggest combining known mutations. In particular, Evans et al. and the ‘113 claims disclose sequence variation of 80% sequence identity, permitting extensive sequence variability within FGF-2 mutant polypeptides. A fusion protein according to instant claim 9 containing instant SEQ ID NO: 4 (a mutant FGF-2 suggested by the ‘113 claims in view of the prior art), pharmaceutical compositions containing instant SEQ ID NO: 4 (a mutant FGF-2 suggested by the ‘113 claims in view of the prior art), and hydrogels containing instant SEQ ID NO: 4 (a mutant FGF-2 suggested by the ‘113 claims in view of the prior art) according to instant claim 21 would have been obvious over the ‘113 claims in view of Bogin et al. and Evans et al.
The instant claims are not patentably distinct from the issued claims in view of the prior art.
Applicant’s arguments are not persuasive for the same reasons as set forth above with respect to the obviousness rejection and the Thallapuranam Declaration.
No unexpected results have been established.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE P ALLEN whose telephone number is (571)272-0712. The examiner can normally be reached 7:00-3:30 EST Monday-Friday.
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/Marianne P Allen/Primary Examiner, Art Unit 1647
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