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 .
Response to Election/Restriction filed on August 29, 2025 is acknowledged.
Claims 1, 7, 26, 28-31, 37, 63, 65-68, 70-73 and 75-80 have been cancelled.
New claims 81-93 have been added.
Claims 17, 20, 58, 64, 69, 74 and 81-93 are pending in this application.
Restriction
Applicant’s election without traverse of Group 2 (claims 17, 20, 64 and 69) and SEQ ID NO: 177 wherein X1, X2, X3 and X4 are each (S)-a-(4’-pentenyl)alanine, the sidechains of X1 and X2 are crosslinked to each other and the sidechains of X3 and X4 are crosslinked to each other in the reply filed on August 29, 2025 is acknowledged. Applicant indicates that claims 17, 20, 64, 69, 83-85 and 88-91 read on the elected group and species. Restriction is deemed to be proper and is made FINAL in this office action. Claims 58, 74, 82, 86-87 and 92-93 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions and species, there being no allowable generic or linking claims. Claims 17, 20, 64, 69, 81, 83-85 and 88-91 are being examined on the merits in this office action. Instant SEQ ID NO: 110 is known in the art.
Objections
7. The drawings are objected to because some of the figures have shadings that make the figures hard to see (see FIG. 2, 4, 5 and 16C, for example). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
8. Claim 17 is objected to for the following: Claim 7 recites, …(i) positions 13, 20, and 27…” This is missing a semicolon after the recitation. Applicant is required to correct this to recite, “…(i) positions 13, 20, and 27;…”
Rejections
U.S.C. 112(b)
9. 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.
10. Claim 17, 20, 64, 69, 81, 83-85 and 88-91 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.
11. Claim 17 recites parenthetical expression “(where position 1 is the N-terminal Serine and position 36 is the C-terminal Leucine)". The metes and bounds of claim 1 is rendered vague and indefinite by the parenthetical recitation of "( where position 1 is the N-terminal Serine and position 36 is the C-terminal Leucine)” because it is unclear as to whether the limitation is part of the instantly claimed subject matter. See MPEP § 2173.05(d).
12. Claim 17 recites, “…(A) wherein if one or more of positions 4, 8, 10, 13, 15, 17, and 18 of SEQ ID NO:110 if not substituted by an a,a-disubstituted non-natural amino acid with olefinic side chains are not substituted or substituted by a conservative amino acids;…wherein one or more of the remaining positions in SEQ ID NO:110 can be substituted by any amino acid;…wherein the structurally-stabilized polypeptide is 15 to 100 amino acids in length; and…has one or more of the properties…(i) binds a recombinant 5-helix bundle…(ii) disrupts the interaction between the 5 helix bundle…and/or (vi) inhibits infection of a cell by SARS-CoV-2.” The metes and bounds of the claim is unclear. It is unclear what the recitation if one or more of positions 4, 8, 10, 13, 15, 17, and 18 of SEQ ID NO:110 if not substituted by an a,a-disubstituted non-natural amino acid with olefinic side chains are not substituted or substituted by a conservative amino acids encompasses. The recitation of “if not substituted…are not substituted” already implies that the positions are not substituted. Therefore, it is unclear if Applicant is reciting that one or more of positions 4, 8, 10, 13, 15, 17, and 18 of SEQ ID NO:110 is not substituted or is substituted by a conservative amino acid substitution. Because claims 20, 64, 69, 81, 83-85 and 88-91 depend from indefinite claim 17 without clarifying the point of confusion, these too are rejected.
U.S.C. 112(a)
13. 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.
14. Claims 17, 64 and 69 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.
The courts have stated:
“To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP 2163.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co., the court stated:
“A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials. Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284-85 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus. . . ."). Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representative, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gostelli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618.
In the instant case, the claims are drawn to a structurally-stabilized polypeptide or a pharmaceutically acceptable salt thereof comprising an amino acid sequence that is at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 94% identical to sequence set forth in the SEQ ID NO: 110…wherein the structurally-stabilized polypeptide is 15 to 100 amino acids in length; and wherein the structurally-stabilized polypeptide has one or more of the properties listed below: (i) binds a recombinant 5- helix bundle of SARS-CoV-2 S protein; (ii) disrupts the interaction between the 5 helix bundle and SEQ ID NO: 258; (iii) is alpha-helical; (iv) is protease resistant; (v) inhibits fusion of SARS-CoV-2 with a host cell; and/or (vi) inhibits infection of a cell by SARS-CoV-2. The generic statement an amino acid sequence that is at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 94% identical to sequence set forth in the SEQ ID NO: 110 does not provide ample written description for the compounds since the claims do not describe a single structural feature. The specification does not clearly define or provide examples of what qualify as compounds of the claimed invention.
As stated earlier, the MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic. It is unquestionable claim 17 is broad generics with respect all possible compounds encompassed by the claims. The possible structural variations are limitless to any class of peptide or a peptide-like molecule that can form cross-linking or can be cross-linked, and make up the class of polypeptides. It must not be forgotten that the MPEP states that if a peptide is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. Here, though the claims may recite some functional characteristics, the claims lack written description because there is no disclosure of a correlation between function and structure of the compounds beyond compounds disclosed in the examples in the specification. Moreover, the specification lack sufficient variety of species to reflect this variance in the genus since the specification does not provide any examples peptides having at least 55%, 60%, 65%, 70%, 75% and 80% sequence identity to instant SEQ ID NO: 110. The specification is void of organic molecules that functions as a peptide-like molecule that qualify for the functional characteristics claimed as a peptide or a peptide-like molecule or other peptidic molecules that can be cross-linked, and other synthetic peptide or peptide-like molecule that can function as amino acids.
The specification is limited to SEQ ID NOs: 175-180 for peptides having at least 85% identity to instant SEQ ID NO: 110. The working example describes instant SEQ ID NOs: 175-180 that falls within a peptide having at least 85% sequence identity to SEQ ID NO: 110 (see Examples 1-16). Instant SEQ ID NO: 110 is a 36mer peptide sequence having a clearly defined peptide sequence. A peptide having at least 55% sequence identity to SEQ ID NO: 110 implies that 36 x 0.55 = 20 residues that are the same. This implies that 36-20 = 16 residues can be different. For at least 60% implies that 22 residues are the same; for at least 65% sequence identity implies that 24 residues are the same; for at least 70% implies that 26 residues are the same; for at least 75% implies that 27 residues must be the same; and for at least 80% implies that 29 residues must be the same. Description of SEQ ID NOs: 175-180 is not sufficient to encompass numerous other proteins and proteases that belong to the same genus. For example, there are varying lengths, varying amino acid compositions, and numerous distinct qualities that make up the genus. There are 20 naturally occurring amino acids. Thus, 16 residue differences (for example, for at least 55% sequence identity to SEQ ID NO: 110) will be 1620 = 1.21 x 1024 different possibilities. There is not sufficient amount of examples provided to encompass the numerous characteristics of the whole genus claimed.
As disclosed by Yampolsky et al (Genetics, 2005, 170: 1459-1472), there are exchangeability rate for each amino acid substitution (see Table 3). And each amino acid substitution will have an effect on the peptide activity (see throughout the reference, for example, pp. 1465-1466).
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate"). Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
35 U.S.C. 103
15. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
16. 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.
17. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
18. 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.
19. Claim(s) 17 and 69 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xia et al (Sci. Adv., April 10, 2019, 5: 1-15) in view of Debnath et al (US 2009/0281041) and Mangold et al (Journal of the American Chemical Society, 2014, 136, 12469-12478).
20. Xia et al teach an EK1 polypeptide sequence that is 100% identical instant SEQ ID NO: 110 (see abstract and Fig. 5B). Xia et al teach that EK1, the optimized form of OC43-HR2P, showed substantially improved pan-CoV fusion inhibitory activity and pharmaceutical properties. Crystal structures indicated that EK1 can form a stable six-helix bundle structure with both short a-HCoV and long b-HCoV HR1s, further supporting the role of HR1 region as a viable pan-CoV target site (see abstract). Xia et al further teach that EK1, a modified OC43-HR2P peptide, has improved fusion inhibitory activity and increased solubility (see p. 3, right column, 1st full paragraph), EK1 peptide potently inhibits multiple CoV cell-cell fusion and blocks various pseudotyped and live CoV infection (see p. 3, right column bottom to pp. 4-5), and EK1 exhibits broad anti-HCoV activity in vivo (see p. 5, left column, 2nd full paragraph to right column, 1st full paragraph), meeting the limitation of instant claims 17 and 69, in part.
The difference between Xia et al and the claims is that Xia et al do not teach a, a-disubstituted non-natural amino acids with olefinic side chains.
21. However, Debnath et al teach a peptide comprising a sequence from 14 to 21 amino acids in length, wherein two of the amino acids are unnatural amino acids having either R or S stereochemistry at the a-carbon wherein the a-carbon of the unnatural amino acids comprises a methyl group and an olefinic group, where the two olefinic groups of the unnatural amino acids are on the same side of the a-helix and are joined to form a cross-link the two unnatural amino acids…(see claim 1, for example), wherein said unnatural amino acid is (S)-a-2-(2’pentenyl)alanine or (R)-a-2-(2’-octenyl)alanine (see claim 2, for example). Debnath et al teach the following:
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(see paragraph [0042]). Debnath et al further teach that the peptides are anti-viral cell-penetrating peptides (see TITLE, for example).
In regards to the recitation: (i) binds a recombinant 5- helix bundle of SARS-CoV-2 S protein; (ii) disrupts the interaction between the 5 helix bundle and SEQ ID NO: 258; (iii) is alpha-helical; (iv) is protease resistant; (v) inhibits fusion of SARS-CoV-2 with a host cell; and/or (vi) inhibits infection of a cell by SARS-CoV-2, this is inherent property of instant SEQ ID NO: 110, having an a,a-disubstituted olefinic amino acids. The MPEP § 2112 states: “Once a reference teaching product appearing to be substantially identical is made the basis of a rejection, and the Examiner presents evidence or reasoning tending to show inherency, the burden shifts to the Applicant to show an unobvious difference ‘[t]he PTO can require an Applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on inherency’ under 35 U.S.C. 102, on prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same...[footnote omitted].” The burden of proof is similar to that required with respect to product-by-process claims. In re Fitzgerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980) (quoting In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977)).”
22. Additionally, Mangold et al teach that olefin metathesis has emerged as a promising strategy for modulating the stability and activity of biologically relevant compounds (see abstract). Mangold et al teach that peptide and protein modification using olefin metathesis has shown promise (see for example, p. 12472, left column, 1st full paragraph). Mangold et al teach for example, a peptide consisting of two sterochemically defined a,a-disubstituted olefinic amino acids separated by one turn of a helix (i.e., olefins positioned at residues 1 and I + 4) that, upon ring closure, would generate a 21-membered macrocycle (see for example, p. 12474, right column, bottom). Mangold et al teach that the non-natural amino acids Fmoc-(S)-2-(4-pentenyl)alanine incorporations at both residues i and i + 4 (see p. 12478, “(125)”).
23. Therefore, it would have been obvious to one of ordinary skill in the art to combine the teachings of Xia et al, Debnath et al and Mangold et al to arrive at a structurally-stabilized polypeptide or a pharmaceutically acceptable salt thereof comprising a peptide sequence set forth in SEQ ID NO: 110, wherein amino acids at positions replaced by a,a-disubstituted non-natural amino acids with olefinic side chains, because all references teach peptides, both Xia et al and Debnath et al teaching antiviral peptides. One of ordinary skill in the art would be motivated to combine with a reasonable expectation of success, since Debnath et al teach that “a chemical approach, called hydrocarbon stapling, overcomes the tendency of short peptides to lose their critical three-dimensional structure—and their ability to function as desired…a-methylated amino acids containing olefinic side chains of varying length are introduced at the (i) and either (i + 4) or (i + 7) positions of the peptide sequence and then cyclized by olefin metathesis…making the peptides more resistant to degradation and enabling their cellular uptake, the hydrocarbon staple overcomes some of the classic shortcomings of peptide therapeutics. Stapled peptides retain their natural shape, are resistant to degradation, and can enter and exert their intended function in cells” (see paragraph [0042]). Mangold further teach that olefin metathesis modulates the stability and activity of biologically relevant compounds (see for example, abstract). One of ordinary skill in the art would have a reasonable expectation of success, since by incorporating the a,a-disubstituted non-natural amino acids with olefinic side chains in the peptides and stapled peptides would increase the stability and activity, and additionally, make the peptides more resistant to degradation and enables their cellular uptake. Therefore, it is deemed that combined art is prima facie obvious over instant claims 17 and 69.
24. Claims 17, 64 and 69 is/are rejected under 35 U.S.C. 103 as being unpatentable over Xia et al (Sci. Adv., April 10, 2019, 5: 1-15) in view of Debnath et al (US 2009/0281041) and Mangold et al (Journal of the American Chemical Society, 2014, 136, 12469-12478) as applied to claims 17 and 69 above, and further in view of Carnahan et al (WO 2007/005249).
25. The teachings of Xia et al in view of Debnath et al and Mangold et al, are described above. The difference between the references and instant claim is that the references do not teach a nanoparticle.
26. However, Carnahan et al teach a branching structure with at least three functional groups comprising glycerol, citric acid, malic acid, amino acids, peptides, synthetic peptide analogs…branched structure with either olefinic, electrophilic or nucleophilic groups, in the presence of functionalized or nonfunctionalized nanoparticles (see page 48, 3rd full paragraph).
27. Therefore, it would have been obvious to one of ordinary skill in the art to combine the teachings of Xia et al, Debnath et al, Mangold et al and Carnahan et al to arrive at a structurally-stabilized polypeptide or a pharmaceutically acceptable salt thereof comprising a peptide sequence set forth in SEQ ID NO: 110, wherein amino acids at positions replaced by a,a-disubstituted non-natural amino acids with olefinic side chains, because all references teach peptides, both Xia et al and Debnath et al teaching antiviral peptides. One of ordinary skill in the art would be motivated to combine with a reasonable expectation of success, since Carnahan et al teach that branching structures with olefinic structures can be in the presence of functionalized or nonfunctionalized nanoparticles. One of ordinary skill in the art would have a reasonable expectation of success, since nanoparticles with branching structures with at least three functional groups (amino acids, peptides, synthetic peptide analogs) and branched structures with olefinic side chains can be achieved. Therefore, it is deemed that combined art is prima facie obvious over instant claims 17, 64 and 69.
.
CONCLUSION
No claim is allowed.
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/JULIE HA/Primary Examiner, Art Unit 1654
11/10/2025