0DETAILED 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 October 27, 2025 has been entered.
Status of the Claims
Claims 1-42 were originally filed May 7, 2021.
The amendment received March 11, 2022 canceled claims 2, 6, and 9-14 and amended claims 3-5, 7, 15, 16, and 24.
Please note: Claims 29-42 are absent from the claims received March 11, 2022. See MPEP § 608.01(j).
The amendment received January 26, 2024 canceled claim 1; amended claims 3-5, 7, 8, and 15-24; and added “new” claim 29.
Please note: Claim 29 can not be considered new since the original claim set had 42 claims. Claims 19-23 have improper status identifiers (i.e. “withdrawn” instead of “withdrawn, currently amended”).
Please note: claims should be in descending order (i.e. dependent claims should be dependent on a preceding claim; see MPEP § 608.01(n); see claims 3, 5, 7, 15, 17, and 19-23).
It is respectfully suggested that claims 1-42 be canceled, new claim 43 be independent, and additional new claims should be dependent on independent new claim 43.
The amendment received July 8, 2024 canceled claims 1-42 and added new claims 43-61.
The amendment filed December 3, 2024 amended claims 43, 44, 47, 52, 54, 55, and 57 and canceled claim 51.
The amendment received July 1, 2025 amended claim 43 and canceled claim 57.
The amendment received October 27, 2025 amended claims 43 and 53 and canceled claims 44, 46-49, 52, and 54-56.
Please note: claim 61 has an improper status identifier of “(Previously Presented)”. Claim 61 should have a status identifier of withdrawn.
Claims 43, 45, 50, 53, and 58-61 are currently pending
Claims 43, 45, 50, 53, and 58-60 are currently under consideration.
Election/Restrictions
Applicants elected, without traverse, Group II (method) in the reply filed on January 26, 2024. 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)).
Applicants elected, without traverse, C16 acyl, VVAA (SEQ ID NO: 4); KKK; and SEQ ID NO: 1 as the species of bioactive peptide amphiphile (PA); C16 acyl, VVAA (SEQ ID NO: 4); KKK; and SEQ ID NO: 1 as the species of charged peptide amphiphile (PA); 100% by mass of bioactive PA; SCA1; and parenterally as the species in the reply filed on January 26, 2024. 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)).
Claim 61 is 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 January 26, 2024.
Please note: applicants’ election of C16 acyl, VVAA (SEQ ID NO: 4); KKK; and SEQ ID NO: 1 as the species of charged peptide amphiphile (PA) and 100% by mass of bioactive PA contradict one another (i.e. if the peptide amphiphile nanofiber only contains bioactive PA, then a charged PA should not have been elected).
Please note: applicants inserted nonelected species into independent claim 43 and requested to elect 40-60% bioactive peptide amphiphile and 60-40% charged PA. Therefore, claims 52-57 are rejoined.
Priority
The present application is a 371 (National Stage) of PCT/US2019/060466 filed November 8, 2019 which claims the benefit of 62/758,219 filed November 9, 2018.
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.
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.
Declaration
The declaration under 37 CFR 1.132 filed October 27, 2025 is insufficient to overcome the rejection of claims 43, 45, 50, 53, and 58-60 based upon the rejections of record below (please refer to the Arguments and Response sections below).
New Objections Due to Amendment
Claim Objections
Claims 43, 45, 50, 53, and 58-60 are objected to because of the following informalities: “30% to 20% by mass” should read “20% to 30% by mass”. Appropriate correction is required.
Claim 45 is objected to because of the following informalities: the claim is dependent on cancelled claim 44. Appropriate correction is required.
Claim 53 is objected to because of the following informalities: the claim is dependent on cancelled claim 52. Appropriate correction is required.
Please note: for examination purposes, claims 45 and 53 will be treated as if the dependency is to independent claim 43.
Withdrawn Rejection
The rejection of claims 43-50, 52-56, and 58-60 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement (new matter) regarding the lack of support in the original specification for molar mass or mol/mol.
New Rejections Due to Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 43, 45, 50, 53, and 58-60 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection. Support in the originally filed specification was not found for 20% to 30% by mass charged peptide amphiphile. Charged peptide amphiphile is a genus. Acidic and basic peptide amphiphile are subgenuses of charged peptide amphiphile. While acidic and basic peptide amphiphiles have mass percentages in the originally filed specification, the genus of charged peptide amphiphile does not.
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.
Claims 43, 45, 50, 53, and 58-60 are 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 present SEQ ID NO: 1. For example, it is unclear how the percent identity and the 50mer or less are related.
Claim 50 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 present SEQ ID NO: 1. For example, it is unclear what the length limit for the VEGF peptide of SEQ ID NO: 1 is (see above wherein any N- or C-terminal additions are possible).
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 50 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 50 depends on independent claim 43. Independent claim 43 requires a length limit of a 50mer or less. Claim 50 is interpreted as requiring 100% identity to present SEQ ID NO: 1 with any N- or C-terminal additions. Therefore, it is unclear if present claim 50 limits the 50mer of independent claim 43 or not. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 43, 45, 50, 53, and 58-60 are rejected under 35 U.S.C. 103 as being unpatentable over Webber et al. U.S. Patent Application Publication 2013/0101628 published April 25, 2013; Cvetanovic et al., 2011, VEGF ameliorates the ataxic phenotype in spinocerebellar ataxia type 1 (SCA1) mice, Nat Med, 17(11): 1445-1447; Cui et al., 2010, Self-Assembly of Peptide Amphiphiles: From Molecules to Nanostructures to Biomaterials, Biopolymers, 94(1): 1-18; and Zhao et al., 2010, Molecular self-assembly and applications of designer peptide amphiphiles, Chem Soc Rev, 39: 3480-3498.
For present claims 43, 45, 50, 53, and 58-60, Webber et al. teach methods of administering to a subject in need thereof a bioactive peptide amphiphile filament/nanofiber comprising a lipophilic/hydrophobic non-peptide segment including C16 acyl; a structural peptide segment that confers the ability to form a b-sheet secondary structure including VVAA (V2A2; SEQ ID NO: 19; present SEQ ID NO: 4); a charged peptide segment/spacer including KKK (K3; triple lysine); and a VEGF peptide KLTWQELYQLKYKGI (SEQ ID NO: 2; present SEQ ID NO: 1) wherein administration is intravenously, intramuscularly, subcutaneous (please refer to the entire specification particularly the abstract; paragraphs 4, 7-17, 31, 37-45, 69, 83-87, 91, 98-101, 103; Examples).
However, Webber et al. do not teach utilizing the VEGF nanofibers to treat spinocerebellar ataxia (SCA1).
For present claims 43, 45, 50, 53, and 58-60, Cvetanovic et al. teach treating spinocerebellar ataxia (SCA1) via administering VEGF (please refer to the entire reference particularly the abstract; pages 1446 and 1447; Figure 2).
For present claims 43, 45, 50, 53, and 58-60, Cui et al. teach that PA assembly can be altered via various parameters including co-assembly of two different PAs at different mixing ratios to provide different characteristics including thermal stability, assembly final structure, size, aggregate formation, etc. (please refer to the entire reference particularly the abstract; Introductions; sections 2.1, 2.2, 2.4; Figures 1, 2).
For present claims 43, 45, 50, 53, and 58-60, Zhao et al. teach that PA assembly can be altered via utilizing two different PAs and varying the ratios including 2:1, 1:1, etc. (please refer to the entire reference particularly the abstract; Introduction; sections 2, 3, 4.4).
"The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." See In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) and In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. See Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (reference disclosing inclusion of a particular component teaches compositions that both do and do not contain that component).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."). See In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.").
The claims would have been obvious because the substitution of one known element (i.e. one class of VEGF related diseases) for another (i.e. species of SCA1) would have yielded predictable results (i.e. treatment of the VEGF related disease with a VEGF nanofiber) 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. administering VEGF nanofibers to patients with a VEGF related disease; co-assembly of two different PAs) was recognized as part of the ordinary capabilities of one skilled in the art. 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 Webber et al.; Cvetanovic et al.; Cui et al.; and Zhao et al. for claims 43, 45, 50, 53, and 58-60 were considered but are not persuasive for the following reasons.
Applicants contend that the 50:50 molar ratio data provided in the 37 CFR §1.132 Declaration by Dr. Stupp received on July 1, 2025 was in error and that the actual ratio is 3:1 (i.e. 75% by mass bioactive PA and 25% by mass charged PA). The declaration utilizes 25% C16V2A2K3 and 75% C16V2A2K3-GKLTWQELYQLKYKGI (i.e. VEGF-PA1:PA1 of 3:1). The declaration states that the combination resulted in smaller micells with less aggregation (see Figures A and B). Applicants contend that smaller micell size and reduced aggregation would be beneficial for administration to the central nervous system to improve biodistribution. Applicants state that Cui et al. and Zhao et al. do not teach combining VEGF-PA and PA. Applicants contend that the specific % mass and/or ratios are not taught in the prior art.
Applicants’ arguments are not convincing since the teachings of Webber et al., Cvetanovic et al., Cui et al, and Zhao et al. render the method of the instant claims prima facie obvious.
First and foremost, it is suspect that applicants “inadvertent error” is what applicants are relying on for unexpected results. If applicants supplied an “inadvertent error” once, how is the examiner of record to trust any data supplied by applicants.
Due to clarity issues with Figure A, it is difficult to evaluate the results. It does appear that aggregation is reduced, but size can not be evaluated due to clarity issues with Figure A. The results in Figure B could be due to reduced aggregation and not reduced size.
Please refer to the references of Cui et al. and Zhao et al. which teach co-assemblies of different PAs at different concentrations/ratios which result in different sizes and differences in aggregation.
Furthermore, it is respectfully noted that unexpected results must be commensurate in scope with the present claims. The percentages in independent claim 43 are broader in scope than the results in Figures A and B (i.e. 70-80% mass for the bioactive peptide amphiphile in independent claim 43; 75% in Figures A and B; 20-30% mass for charged peptide amphiphile in independent claim 43 and 25% in Figures A and B). In addition, the scope of the PAs is broader in scope in the present claims than in Figures A and B (i.e. PA is C6-C20 acyl, VVAA, and KKK in independent claim 43 and C16V2A2K3 in Figures A and B). Moreover, the scope of the PA-VEGF is broader in scope in the present claims than in Figures A and B (i.e. PA is C6-C20 acyl, VVAA, KKK in independent claim 43 and C16V2A2K3 in Figures A and B; VEGF is a peptide comprising at least 90% identity to KLTWQELYQLKYKGI (SEQ ID NO: 1) and wherein the VEGF peptide is 50 amino acids in length or less in independent claim 43 and GKLTWQELYQLKYKGI in Figures A and B).
The prior art (e.g. Cui et al. and Zhao et al.) teaches that it is common practice in forming PAs to alter the concentrations/ratios or co-assembled PAs to alter properties including aggregates, size, shape, etc. Therefore, the results are not unexpected but part of the common knowledge in the prior art.
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."). See In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.").
The present claims do not require administration to the CNS or targeting the CNS with the exception of perhaps dependent claim 59. However, Cvetanovic et al. teach treating spinocerebellar ataxia (SCA1) via administering VEGF. Therefore, it appears that the prior art teaches the ability of large polypeptides to target the CNS. Furthermore, there are an abundance of methods in the prior art to target the CNS with self-assembling peptide amphiphiles. Cui et al. teach utilizing PAs for neural regeneration (see section 4.1).
See also Ellis-Behnke et al., 2006, Nano neuro knitting: Peptide nanofiber scaffold for brain repair and axon regeneration with functional return to vision, PNAS, 103(13): 5054-5059; Mazza et al., 2015, Peptide Nanofiber Complexes with siRNA for Deep Brain Gene Silencing by Stereotactic Neurosurgery, ACS Nano, 9(2): 1137-1149; and Wang et al., 2014, A novel artificial nerve graft for repairing long-distance sciatic nerve defect: a self-assembling peptide nanofiber scaffold-containing poly(lactic-co-glycolic acid) conduit, Neural Regeneration Research, 9(24): 2132-2141.
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).
Cui et al. teach combining PAs with growth factors (i.e. genus encompassing VEGF-PA/PA-VEGF; see section 2.1). Cui et al. teach coassembly of multiple PAs utilizing various mixing ratios (see section 2.4). Zhao et al. teach PAs of different diameters including 10 nm, 40-80 nm, 100-200 nm, etc. (see section 3.1). Zhao et al. teach mixing different PAs in different ratios which alters size and aggregation (see “Synergistic effect”).
Claims 43, 45, 50, 53, and 58-60 are rejected under 35 U.S.C. 103 as being unpatentable over Webber et al. U.S. Patent Application Publication 2013/0101628 published April 25, 2013; Li U.S. Patent Application Publication 2011/0318365 published December 29, 2011; Cui et al., 2010, Self-Assembly of Peptide Amphiphiles: From Molecules to Nanostructures to Biomaterials, Biopolymers, 94(1): 1-18; and Zhao et al., 2010, Molecular self-assembly and applications of designer peptide amphiphiles, Chem Soc Rev, 39: 3480-3498.
For present claims 43, 45, 50, 53, and 58-60, Webber et al. teach methods of administering to a subject in need thereof a bioactive peptide amphiphile filament/nanofiber comprising a lipophilic/hydrophobic non-peptide segment including C16 acyl; a structural peptide segment that confers the ability to form a b-sheet secondary structure including VVAA (V2A2; SEQ ID NO: 19; present SEQ ID NO: 4), AAVV (present SEQ ID NO: 3), and AAAVVV (present SEQ ID NO: 2); a charged peptide segment/spacer including KKK (K3; triple lysine) or KKKG; and a VEGF peptide KLTWQELYQLKYKGI (SEQ ID NO: 2; present SEQ ID NO: 1) wherein administration is intravenously, intramuscularly, subcutaneous (please refer to the entire specification particularly the abstract; paragraphs 4, 7-17, 31, 37-45, 69, 83-87, 91, 98-101, 103; Examples).
However, Webber et al. do not teach utilizing the VEGF nanofibers to treat spinocerebellar ataxia (SCA).
For present claims 43, 45, 50, 53, and 58-60, Li teaches methods of administering VEGF including acyl derivatives to treat neurodegenerative diseases including spinocerebellar ataxia wherein administration is parenteral including intramuscular, intravenous, or subcutaneous (please refer to the entire specification particularly the abstract; paragraphs 2-9, 46, 48-56, 59-72, 74, 76, 79, 88, 103, 104, 106, 134-136, 139, 140, 146, 150).
For present claims 43, 45, 50, 53, and 58-60, Cui et al. teach that PA assembly can be altered via various parameters including co-assembly of two different PAs at different mixing ratios to provide different characteristics including thermal stability, assembly final structure, size, aggregate formation, etc. (please refer to the entire reference particularly the abstract; Introductions; sections 2.1, 2.2, 2.4; Figures 1, 2).
For present claims 43, 45, 50, 53, and 58-60, Zhao et al. teach that PA assembly can be altered via utilizing two different PAs and varying the ratios including 2:1, 1:1, etc. (please refer to the entire reference particularly the abstract; Introduction; sections 2, 3, 4.4).
"The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." See In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) and In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. See Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (reference disclosing inclusion of a particular component teaches compositions that both do and do not contain that component).
Generally, differences in concetnration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."). See In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.").
The claims would have been obvious because the substitution of one known element (i.e. one class of VEGF related diseases) for another (i.e. species of SCA) would have yielded predictable results (i.e. treatment of the VEGF related disease with a VEGF nanofiber) 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. administering VEGF nanofibers to patients with a VEGF related disease; co-assembly of two different PAs) was recognized as part of the ordinary capabilities of one skilled in the art. 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 Webber et al.; Li; Cui et al.; and Zhao et al. for claims 43, 45, 50, 53, and 58-60 were considered but are not persuasive for the following reasons.
Applicants contend that the 50:50 molar ratio data provided in the 37 CFR §1.132 Declaration by Dr. Stupp received on July 1, 2025 was in error and that the actual ratio is 3:1 (i.e. 75% by mass bioactive PA and 25% by mass charged PA). The declaration utilizes 25% C16V2A2K3 and 75% C16V2A2K3-GKLTWQELYQLKYKGI (i.e. VEGF-PA1:PA1 of 3:1). The declaration states that the combination resulted in smaller micells with less aggregation (see Figures A and B). Applicants contend that smaller micell size and reduced aggregation would be beneficial for administration to the central nervous system to improve biodistribution. Applicants state that Cui et al. and Zhao et al. do not teach combining VEGF-PA and PA. Applicants contend that the specific % mass and/or ratios are not taught in the prior art. Applicants contend that Li discredits utilizing other VEGF family members which have neural protective effects because the other VEGF family members stimulate undesired angiogenesis and blood vessel permeability.
Applicants’ arguments are not convincing since the teachings of Webber et al., Li, Cui et al, and Zhao et al. render the method of the instant claims prima facie obvious.
First and foremost, it is suspect that applicants “inadvertent error” is what applicants are relying on for unexpected results. If applicants supplied an “inadvertent error” once, how is the examiner of record to trust any data supplied by applicants.
Due to clarity issues with Figure A, it is difficult to evaluate the results. It does appear that aggregation is reduced, but size can not be evaluated due to clarity issues with Figure A. The results in Figure B could be due to reduced aggregation and not reduced size.
Please refer to the additional references of Cui et al. and Zhao et al. which teach co-assemblies of different PAs at different concentrations/ratios which result in different sizes and differences in aggregation.
Furthermore, it is respectfully noted that unexpected results must be commensurate in scope with the present claims. The percentages in independent claim 43 are broader in scope than the results in Figures A and B (i.e. 70-80% mass for the bioactive peptide amphiphile in independent claim 43; 75% in Figures A and B; 20-30% mass for charged peptide amphiphile in independent claim 43 and 25% in Figures A and B). In addition, the scope of the PAs is broader in scope in the present claims than in Figures A and B (i.e. PA is C6-C20 acyl, VVAA, and KKK in independent claim 43 and C16V2A2K3 in Figures A and B). Moreover, the scope of the PA-VEGF is broader in scope in the present claims than in Figures A and B (i.e. PA is C6-C20 acyl, VVAA, KKK in independent claim 43 and C16V2A2K3 in Figures A and B; VEGF is a peptide comprising at least 90% identity to KLTWQELYQLKYKGI (SEQ ID NO: 1) and wherein the VEGF peptide is 50 amino acids in length or less in independent claim 43 and GKLTWQELYQLKYKGI in Figures A and B).
The prior art (e.g. Cui et al. and Zhao et al.) teaches that it is common practice in forming PAs to alter the concentrations/ratios or co-assembled PAs to alter properties including aggregates, size, shape, etc. Therefore, the results are not unexpected but part of the common knowledge in the prior art.
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."). See In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.").
The present claims do not require administration to the CNS or targeting the CNS with the exception of perhaps dependent claim 59. However, Li teaches methods of administering VEGF including acyl derivatives to treat neurodegenerative diseases including spinocerebellar ataxia wherein administration is parenteral including intramuscular, intravenous, or subcutaneous. Therefore, it appears that the prior art teaches the ability of large polypeptides to target the CNS. Furthermore, there are an abundance of methods in the prior art to target the CNS with self-assembling peptide amphiphiles. Cui et al. teach utilizing PAs for neural regeneration (see section 4.1).
See also Ellis-Behnke et al., 2006, Nano neuro knitting: Peptide nanofiber scaffold for brain repair and axon regeneration with functional return to vision, PNAS, 103(13): 5054-5059; Mazza et al., 2015, Peptide Nanofiber Complexes with siRNA for Deep Brain Gene Silencing by Stereotactic Neurosurgery, ACS Nano, 9(2): 1137-1149; and Wang et al., 2014, A novel artificial nerve graft for repairing long-distance sciatic nerve defect: a self-assembling peptide nanofiber scaffold-containing poly(lactic-co-glycolic acid) conduit, Neural Regeneration Research, 9(24): 2132-2141.
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).
Cui et al. teach combining PAs with growth factors (i.e. genus encompassing VEGF-PA/PA-VEGF; see section 2.1). Cui et al. teach coassembly of multiple PAs utilizing various mixing ratios (see section 2.4). Zhao et al. teach PAs of different diameters including 10 nm, 40-80 nm, 100-200 nm, etc. (see section 3.1). Zhao et al. teach mixing different PAs in different ratios which alters size and aggregation (see “Synergistic effect”).
Li does not teach away from utilizing Webber et al. because Li does not discredit any of the teachings of Webber et al. Li cites Carmeliet et al., 2005, Common mechanisms of nerve and blood vessel wiring, Nature, 436: 193-200 (citation 6) and Greenberg et al., 2005, From angiogenesis to neuropathology, Nature, 438: 954-959 (citation 7) which teach that the vascular effects of VEGF can be beneficial in the nervous system. In addition, as applicants are aware (i.e. Puneet Opal) VEGF ameliorates the ataxic phenotype in spinocerebellar ataxia type 1 mice (see Cvetanovic et al., 2012, VEGF ameliorates the ataxic phenotype in spinocerebellar ataxia type 1 (SCA1) mice, Nat Med, 17(11): 1445-1447).
"The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." See In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) and In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. See Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. See In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). Furthermore, "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….". See In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) ("a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.") (internal quotations omitted) (quoting DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009)); and Schwendimann v. Neenah, Inc., 82 F.4th 1371, 1381, 2023 USPQ2d 1173 (Fed. Cir. 2023).
Webber et al. is utilized to teach the specific structure of the PA and the specific structure of the VEGF peptide as presently claimed.
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/AMBER D STEELE/Primary Examiner, Art Unit 1658