G PROTEIN PEPTIDOMIMETICS

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 . Priority Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Information Disclosure Statement The information disclosure statements (IDS) were submitted on 6/16/2023 and 9/18/2023, before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. Claim Status Claims 10-13, 15-28, 31, 33, 34, and 36-38, filed 7/23/2026, are pending. Claims 10-13, 15-28, 31, 33, 34, and 36-38 are under examination. Claim 14 is canceled. Claim Interpretation For purposes of compact prosecution, the narrow “consisting of” language in claim 10 will be construed as necessary for purposes of examination despite the rejections made below. This is supported by the clear intent to resolve rejections under 35 U.S.C. 112(a) from the previous office action. Also for purposes of compact prosecution, line 6 of claim 10 shall be construed to have a semicolon between “N-terminus” and “wherein”. Without such a semi-colon, the claim loses the intended meaning which makes examination fruitless. Claim 23 will be interpreted to recite closed peptide sequences as if “consists of” had been invoked. This is supported by all the amino acids in the sequences being defined amino acids and optional components are not shown to be present in the specification. Claim Objections Claim 10 is objected to because of the following informalities. For clarity, the optional component “…b) optionally at least one basic amino acid at its N-terminus…” is better placed at the end of the claim so it is clear that only this component is optional. Changing the comma to a semicolon also addresses this issue, but that amendment would still be more difficult for a future reader (such as a judge) to understand. Also, when listing the amino acid compositions of the various formulae, it would be more grammatically correct to state them in the format: “…wherein: Formulae VIII is RDX8IQRX7HLX6X5X4X3X2X1…” and so forth. While the intent is clear, and therefore not a source of indefiniteness, these lines do not flow grammatically. Appropriate correction is required. Claim 23 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Previous Claim Rejections (Now Withdrawn) - 35 USC § 112 Claims 10-21, 24-28, 31, 33, 34, and 36 were previously 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. Response to Arguments Applicant’s arguments, see Applicant Reply, page 12, para. 2, filed 7/23/2026, with respect to claims 10-13, 15-21, 24-28, 31, 33, 34, and 36 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. Claim 14 has been canceled, rendering that rejection moot. However, upon further consideration, a new ground of rejection is made below. Claims 10-21, 24-28, 31, 33, and 34 were previously rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for G protein peptidomimetics of formula (VIII) up to 22 amino acids in length and a method of capturing GPCR in an active confirmation the case wherein the G protein peptidomimetic is up to 22 amino acids in length and residues X1a, X2a, X3a, X4a are phenylalanine, tryptophan, cyclohexylalanine, 1-Nal, homoglutamic acid, and 2-Nal, wherein X5 is glutamine, cysteine, the Pra moiety, the Azk moiety, the S5 moiety, the R5 moiety, and the R8 moiety, X6 is arginine, cysteine, the Pra moiety, the Azk moiety, the S5 moiety, the R5 moiety, and the R8 moiety, X7 is methionine, cysteine, the Pra moiety, the Azk moiety, the S5 moiety, the R5 moiety, and the R8 moiety, X8 is isoluecine, cysteine, the Pra moiety, the Azk moiety, the S5 moiety, the R5 moiety, and the R8 moiety does not reasonably provide enablement for the case wherein the G protein peptidomimetic residues X1a, X2a, X3a, X4a are any of the possible claimed alanine derivatives (the contents of Table B) and wherein X5, X6, X7, X8 are any possible olefinic amino acid, any possible side chain with carboxylic acid, any possible amine containing side, any possible amino acid with an alkynyl side chain, or any possible azidated side chain. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. Response to Arguments Applicant’s arguments, see Applicant Reply, page 15, para. 3, filed 7/23/2026, with respect to claims 10-13, 15-21, 24-28, 31, 33, 34, and 36 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. Claim 14 has been canceled, rendering that rejection moot. However, upon further consideration, a new ground of rejection is made below. New 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. Claims 10-13, 15-22, 24-28, 31, 33-34, and 36-38 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. Regarding claim 10, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 10 recites the broad recitation “…and optionally wherein the peptidomimetic comprises at least one covalent tether, the covalent tether being formed from the reaction of an amino acid containing an amine side-chain with an amino acid containing a carboxylic acid group side-chain, or from the reaction between two olefinic amino acids, or from the reaction of an amino acid containing an azidated side-chain with an amino acid containing an alkynyl side-chain, or from the reaction between two amino acids each containing a thiol group side-chain, or from the reaction of an olefinic amino acid with an amino acid containing a thiol group side-chain.”, and the claim also recites “A G protein peptidomimetic or salt thereof comprising consisting of:a) a sequence selected from the group consisting of the sequence of formula (VIII),the sequence of formula (IX), the sequence of formula (X), the sequence of formula (XI), the sequence of formula (XII), the sequence of formula (XIII), the sequence of formula (XIV), the sequence of formula (XV), the sequence of formula (XVI), and the sequence of formula (XVII), and b) optionally at least one basic amino acid at its N-terminus,…” which is the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Specifically, if the optional clause is invoked, then the transitional phrase “comprising” is also invoked, which defeats the purpose of the “consisting of” earlier in the claim. Presumably, “consisting of” was invoked to overcome previous rejections under 112(a), therefore a plausible amendment would be to change the optional language to state “optionally wherein the peptidomimetic further consists of at least one covalent tether…”. Additionally, claim 10 recites other open-ended phrases. These include the phrases “…at least one basic amino acid…” on page 2, line 6, the phrase “…R9 is selected from the group comprising…” on page 5, line 20, “… one or more C1-6 alkyl…” on page 5 line 26, and “…optionally wherein the peptidomimetic comprises at least one covalent tether,…” on page 6 line 26. As described above, these clauses defeat the purpose of the “consisting of” transitional phrase and create a source of indefiniteness because it is not clear whether the scope of the compound is closed or not closed. Also, a comma exists on line 6 between “N-terminus” and “wherein”. Read strictly, this means the formula definitions that follow are also optional, which undermines the likely intent of the claim language. However, until this is corrected, this creates a source of indefiniteness because it means the formula definitions are optional. Consequently, claim 10 is rejected. Regarding claims 11-13 and 15, claim 10 is rejected as described above. Claims 11-13 and 15 do not resolve all the sources of indefiniteness of claim 10. Consequently, claims 11-13 and 15 are rejected. Regarding claims 16 and 17, claim 10 is rejected as described above. Claims 16 and 17 do not resolve all the sources of indefiniteness of claim 10 and repeat one such source. The phrase “…comprising a covalent tether…” is in conflict with the closed nature of “consisting of” in claim 10. It is not clear whether the scope of the compound is closed or not closed. Consequently, claims 16 and 17 are rejected. Regarding claim 18, claim 12 is rejected as described above. Clam 18 does not resolve all the sources of indefiniteness of claim 10. Consequently, claim 18 is rejected. Regarding claims 19-21, claim 10 is rejected as described above. Claims 19-21 do not resolve all the sources of indefiniteness of claim 10. Furthermore, these claims introduce that the G protein “comprises” some particular SEQ ID NO. It is not clear whether the scope of the compound is closed or not closed. Consequently, claims 19-21 are rejected. Regarding claim 22, claim 10 is rejected as described above. Claim 22 recites definite amino acid sequences which eliminates some of the indefiniteness. However, the phrases “…at least one basic amino acid…” on page 2, line 6 and “…optionally wherein the peptidomimetic comprises at least one covalent tether,…” on page 6 line 26 are still relevant. Furthermore, this claim uses the phrase “comprising”. It is not clear whether the scope of the compound is closed or not closed. Consequently, claim 22 is rejected. Regarding claims 24-27, claim 10 is rejected as described above. These claims do not address the indefiniteness of claim 10. Consequently, claims 24-27 are rejected. Regarding claim 28, claim 27 is rejected as described above. This claim does not address the indefiniteness of claim 27 and also uses the phrase “comprising”. It is not clear whether the scope of the compound is closed or not closed. Consequently, claim 28 is rejected. Regarding claims 31, 33, 34, and 36, claim 10 is rejected as described above. These claims do not address the indefiniteness of claim 10. Consequently, claims 31, 33, 34, and 36 are rejected. Regarding claims 37 and 38, claim 10 is rejected as described above. These claims reduce the indefiniteness by claim 37 eliminating R9 for example, but fail to address all the sources of indefiniteness. Consequently, claims 37 and 38 are rejected. Examiner note: Claim 23 is not rejected because of the closed interpretation described above. 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 10-13, 15-21, 24-28, 31, 33-34, and 36-38 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. Regarding claim 10, the G protein peptidomimetic of claim 10 is an extremely large genus because of the number of cyclohexyl alanine analogues disclosed by the specification and claimed by claim 10: “…; R9 is selected from the group comprising OH, halo, Ci-6alkyl, C3-12cycloalkyl, C2-6alkenyl, C1-6 alkoxy, oxo, =CH2, amino, mono- or di- Ci-6alkylamino, haloCl-6alkyl, or two R9 together with the atom to which they are attached may form a C3-12cycloalkyl, C5-12cycloalkenyl, heterocycloalkyl, or C6-12aryl; each of said formed C3-12cycloalkyl, C5-12cycloalkenyl, heterocycloalkyl or C6-12aryl may be optionally substituted by one or more C1-6alkyl…” The phrase “comprising” means the number of possible substituents of R9 is open-ended and therefore has no length limitation. Consequently, this unlimited sequence space will necessarily encompass peptides that no longer possess a G protein peptidomimetic structure. Also, as described above in the indefiniteness rejection, the full scope of the length of the polypeptide of claim 10 is not clear, which reintroduces the open-ended length issue from the previous office action. Furthermore, language such as “…at least one basic amino acid at its N-terminus…” leaves the possibility of many, many such amino acids. This also contributes to the genus size. In this case, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. (MPEP § 2163 (II.A.3.a.ii.)) According to MPEP § 2163 (II.A.3.a.ii.), a "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). As described above, claim 10 recites an extremely large (open-ended and many side chains) genus of peptides. MPEP § 2163 (II.A.3.a.ii.) states that “for inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’” Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus. In the instant case, Applicant reduces many peptides to practice. However, these peptides are limited to 15 residues to 22 residues in length. Furthermore, the primary alanine analogues reduced to practice are 1-Nal, 2-Nal, and cyclohexylalanine. Many of the claimed alanine analogues are significantly larger (van der Waals radius) than cyclohexylalanine and/or possess additional polar regions and electron pairs. None of these cyclohexylalanine analogs are shown to possess the claimed activity. At the time the invention was made, the level of skill for preparing peptides with desired functional properties was high. However, even if a synthesis and selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify peptides that yield polypeptides with the recited properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure (length) provided by the provided species, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what peptide with a particular set of properties would look like structurally. Applicant discloses SEQ ID NOs: 158, 180, 172, 174, 95, 176, 177, 98, 99, 178, 114, and 116. These sequences utilize cyclohexylalanine, 1-Nal, and 2-Nal but not the other side chains from Table B. Therefore, the provided examples only represent a limited structural diversity. Since only a limited number of species of peptides are taught within the claimed genus above, the instant claim above fails the written description requirement. A representative number of species has not been taught to describe this genus. Regarding the peptides, a single point mutation can change the biophysical properties of a peptide: “In summary, we have shown that the structural changes in the fibrillar state of the Aβ42 peptide that are observed to occur upon introduction of single point mutations can be accompanied by changes in the dominance of the microscopic processes by which these aggregates are themselves formed.” (Bolognesi et al. ACS Chem Bio 9:2 (2013) page 381 col. 2 para. 3) and “In summary, while ovispirin-1 and novispirin G-10 both had solution structures that were helical and amphipathic in the presence of TFE, a relatively simple change in their primary structure (a single glycine–isoleucine exchange) had profound effects on their respective toxicities for human erythrocytes and epithelial cells.” (Sawai et al. Protein Eng. 15:3 (2002) page 232 col. 1 para. 3). Furthermore, many sequences allowed by the current scope of the claims, result in non-functional aggregates. Wang (Wang, et al. MAbs. Vol. 1. No. 3. Taylor & Francis, (2009)) discloses a variety of aggregation prone motifs that occur in commercial antibodies (Wang, page 262, Table 2). The scope of the claims currently may incorporate such motifs and result in non-functional aggregates. Given this unpredictability of protein design, the skilled artisan would not have been in possession of the substantial repertoire of peptide species encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of every polynucleotide molecule recited by claim 10. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus. Therefore, claim 10 is rejected. Regarding claim 11, claim 10 is rejected as described above. Claim 11 further recites limitations for variable positions, but does not restrict the sequence space claimed nor restrict the identities of X5-X8. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus and claim 11 is rejected. Regarding claim 12, claim 10 is rejected as described above. Claim 12 recites formula (XII), which is a subset of the peptides claimed by claim 10. However, this does not substantially reduce the genus size because of the potentially open-ended sequence length and the nature of the R9 substituent. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus and claim 12 is rejected. Regarding claim 13, claim 10 is rejected as described above. Claim 13 reduces the options for X5-X7, but does not otherwise reduce the genus size. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus and claim 13 is rejected. Regarding claim 15, claim 10 is rejected as described above. Claim 15 reduces the genus size by eliminating R9. However, the open-ended permutation of claim 10 are still present. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus and claim 15 is rejected. Regarding claims 16-21, these claims place additional structural limitations on the peptide of claim 10, but none of these claims sufficiently reduce the genus size because of the open-ended sequence length and R9 in each case. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus and claims 16-21 are rejected. Regarding claims 24-28, these claims place additional structural limitations on the peptide of claim 10, but none of these claims sufficiently reduce the genus size because of the open-ended sequence length in each case. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus and claims 24-28 are rejected. Regarding claim 31, claim 31 recites a method of capturing GPCR in an active conformation, the method comprising the steps of: a) bringing a G protein peptidomimetic of claim 10 into contact with a GPCR, and b) allowing the G protein peptidomimetic to bind to the GPCR, whereby the GPCR is captured in an active conformation. This claim has the same genus size as claim 10 and therefore is rejected. Regarding claim 33, claim 33 recites a method of crystallizing a complex of a G protein peptidomimetic of claim 10 and a GPCR and optionally a ligand of the GPCR, the method comprising the steps of: a) providing a G protein peptidomimetic of claim 10 and a GPCR, and optionally a ligand of the GPCR, b) allowing the formation of a complex of the G protein peptidomimetic, the GPCR and optionally the ligand, and c) crystallizing the complex of step b) to form a crystal. Claim 33 requires binding activity and claims the same genus size as claims 10 and 31. For the same reasons as claim 31 above, the disclosed examples with binding activity are not representative of the claimed genus. Consequently, one of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus. Therefore, claim 33 is rejected. Regarding claim 34, claim 33 is rejected as described above. Claim 34 does not reduce the genus size of the claimed invention. Consequently, one of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus. Therefore, claim 34 is rejected. Regarding claim 36, claim 36 recites a screening method for identifying compounds capable of interacting with a GPCR comprising a) contacting the GPCR with a test compound and a G protein peptidomimetic of claim 10; b) evaluating binding of the test compound to the GPCR; and c) optionally selecting a test compound that binds to the GPCR as a compound capable of interacting with the GPCR. Claim 36 has the same genus size as claim 10. Consequently, one of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus. Therefore, claim 36 is rejected. Regarding claim 37, claim 10 is rejected as described above. Claim 37 reduces the genus size by eliminating the R9 moiety issue. However, open ended elements remain and the X5-X8 positions still encompass many unrepresented azidated and carboxcyclic acid sides chains. Consequently, one of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus. Therefore, claim 37 is rejected. Regarding claim 38, claim 10 is rejected as described above. Claim 37 reduces the genus size by limiting the X5-X8 positions. However, open ended elements remain and the R9 moiety remains an issue. Consequently, one of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus. Therefore, claim 38 is rejected. Claims 10-13, 15-21, 24-28, 31, 33-34, and 36-38 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for G protein peptpidomimetics of formula (VIII) up to 22 amino acids in length and a method of capturing GPCR in an active confirmation the case wherein the G protein peptidomimetic is up to 22 amino acids in length and residues X1a, X2a, X3a, X4a are phenylalanine, tryptophan, cyclohexylalanine, 1-Nal, homoglutamic acid, and 2-Nal, wherein X5 is glutamine, cysteine, the Pra moiety, the Azk moiety, the S5 moiety, the R5 moiety, and the R8 moiety, X6 is arginine, cysteine, the Pra moiety, the Azk moiety, the S5 moiety, the R5 moiety, and the R8 moiety, X7 is methionine, cysteine, the Pra moiety, the Azk moiety, the S5 moiety, the R5 moiety, and the R8 moiety, X8 is isoluecine, cysteine, the Pra moiety, the Azk moiety, the S5 moiety, the R5 moiety, and the R8 moiety X9 is cysteine, and X10 is aspartic acid, the Pra moiety, the E3 moiety, the S5 moiety, and the Azk moiety, does not reasonably provide enablement for the case wherein the G protein peptidomimetic residues X1a, X2a, X3a, X4a are any of the possible claimed R9 motifs and wherein X5, X6, X7, X8 are any possible olefinic amino acid, any possible side chain with carboxylic acid, any possible amine containing side, any possible amino acid with an alkynyl side chain, or any possible azidated side chain, X9 being any amino acid without a thiol group, or X10 being any possible olefinic amino acid, any possible amino acid with a carboxylic acid, and amine-containing side chain amino acid, or any possible azidated amino acid. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024). These factors include, but are not limited to: The breadth of the claims; The breadth of the claims encompass a G protein peptidomimetic as described by claim 10 and a method of capturing a GPCR in an active conformation, wherein the claimed binder is a peptidomimetic as claimed in claim 10. The total breadth of this peptidomimetic as claimed is described in the written description rejection of claims 31, 33, and 34 above. Specifically, the huge number of R9 permuations and large number of side chains within X5, X6, X7, and X8 make the method of claim 31 very broad. The nature of the invention; The invention is a G protein peptidomimetic and a method of capturing a GPCR in an active confirmation, the method comprising the steps of: a) bringing a G protein peptidomimetic of claim 10 into contact with a GPCR,, and b) allowing the G protein peptidomimetic to bind the GPCR, whereby the GPCR is captured in an active confirmation. The state of the prior art; Due to G protein-receptors being membrane-bound proteins, a large portion of the prior art consists of molecular dynamics simulations. Molecular dynamics simulations predict the importance of the α5 helix: “Next, we examined flexibility change of the G proteins upon coupling to the different receptors. In the Gs protein, the C-terminus of the Gα α5 helix exhibited higher fluctuations when the A2AAR was changed to the A1AR (Figure 1C). In the Gi protein, while the Gα α5 helix became stabilized with lower fluctuations, the α4-β5 loop and switch ΙΙΙ exhibited higher flexibility when the A1AR was changed to the A2AAR (Figure 1D). These regions were shown earlier to be important in activation and receptor recognition of the G protein.” (Wang, et al. The Journal of Physical Chemistry B 123.30: 6462-6473 (2019), page 6467, col. 1, para. 2). Conrad et al. discloses that a great deal of uncertainty surround G protein-coupled receptor binding specificity: “However, we want to emphasize that previous studies have shown that there is no simple GPCR sequence pattern explaining G protein coupling specificity and that at least two additional structural factors may play an important role: (i) Structural studies of GPCRs in complex with different G proteins indicate, that the position and dynamics of helix H6 significantly affect coupling selectivity. (ii) As recently demonstrated for β2AR, transient interactions observed between the GPCR and GDP-bound Gs protein may represent an intermediate on the way to the formation of the final complex and may contribute to coupling specificity. Future studies of H2R in complex with different G proteins or investigations of different G protein binding modes will be required to assess the role of these structural factors for H2R coupling preferences.” (Conrad, et al. International Journal of Molecular Sciences 21.18: 6693 (2020), page 6, para. 2). Wingler et al. reviews characterization efforts over the years and makes the following observation: “Another facet of GPCRs’ versatility is that different agonists of the same receptor can effect qualitatively different patterns of signaling. Classic models of GPCR allostery and activation, describing an equilibrium between a single inactive and a single signaling-competent active conformation, cannot account for the complex pharmacology of these ‘biased ligands’. This has sparked intense interest in what makes the conformations stabilized by biased ligands ‘unique’. In this review, we discuss how data from multiple biophysical approaches are revealing that the breadth of pharmacology observed in GPCR ligands inherently follows from the conformational heterogeneity of GPCRs.” (Wingler, et al. Trends in cell biology 30.9: 736-747 (2020), page 736, para. 2). (D) The level of one of ordinary skill; A person of ordinary skill in the art in the field of fusion proteins is usually at least a Master’s level education. (E) The level of predictability in the art; Protein-protein interactions are generally unpredictable. A single point mutation can change the biophysical properties of a peptide: “In summary, we have shown that the structural changes in the fibrillar state of the Aβ42 peptide that are observed to occur upon introduction of single point mutations can be accompanied by changes in the dominance of the microscopic processes by which these aggregates are themselves formed.” (Bolognesi et al. ACS Chem Bio 9:2 (2013) page 381 col. 2 para. 3) and “In summary, while ovispirin-1 and novispirin G-10 both had solution structures that were helical and amphipathic in the presence of TFE, a relatively simple change in their primary structure (a single glycine–isoleucine exchange) had profound effects on their respective toxicities for human erythrocytes and epithelial cells.” (Sawai et al. Protein Eng. 15:3 (2002) page 232 col. 1 para. 3). Furthermore, many sequences allowed by the current scope of the claims, result in non-functional aggregates. Wang 2 (Wang, et al. MAbs. Vol. 1. No. 3. Taylor & Francis, (2009)) discloses a variety of aggregation prone motifs that occur in commercial antibodies (Wang, page 262, Table 2). The scope of the claims currently may incorporate such motifs and result in non-functional aggregates. (F) The amount of direction provided by the inventor and the existence of working examples and the quantity of experimentation needed to make or use the invention based on the content of the disclosure. Applicant provides a robust number of sample compound in Table 18a. However, these compounds utilize only a fraction of the possible claimed residues. Specifically, Applicant demonstrates enablement for hGlu, Cha, 1-Nal, 2-Nal, Pra, Azk, S5, R5, and R8 as well as the recited common amino acids. Compounds utilizing these motifs are demonstrated as capturing GPCR in an active confirmation by using a radioligand binding assay. Regarding claim 10, claim 10 recites formulae that reference R9 which creates enormous sequence space. Furthermore, X5-X8 encompass a large number of residues. X9 can be any amino acid without a thiol side chain, which is open-ended. X10 can be any olefinic amino acid, any amino acid with a carboxylic acid, any amino acid with an amine side chain any alkynyl amino acid, or any azidated amino acid. Consequently, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims and claim 10 is rejected. Regarding claim 11, claim 10 is rejected as described above. Claim 11 further recites limitations for variable positions, but does not restrict the sequence space claimed by X5-X10. Because of the enormous sequence space encompassed by claim 11, a person of ordinary skill in the art would be required to perform undue experimentation to determine which members of the genus were G protein peptidomimetics after expression and protein folding. Consequently, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims and claim 11 is rejected. Regarding claim 12, claim 12 recites formula (XII), which is a subset of the peptides claimed by claim 10. However, this does not sufficiently reduce the sequence space because R9 is not limited and X5-X10 are not limited. Because of the enormous sequence space encompassed by claim 12, a person of ordinary skill in the art would be required to perform undue experimentation to determine which members of the genus were G protein peptidomimetics after expression and protein folding. Consequently, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with this claim and claim 12 is rejected. Regarding claims 13 and 15, claim 10 is rejected as described above. R9, X9, and X10 are not limited in this claim. Consequently, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims and claims 13 and 15 are rejected. Regarding claims 16-21, these claims place additional structural limitations on the peptide of claim 10, but none of these claims sufficiently reduce the sequence space because of the nature of R9 and X5-X10 as described above. Because of the enormous sequence space encompassed by claims 16-21, a person of ordinary skill in the art would be required to perform undue experimentation to determine which members of the genus were G protein peptidomimetics after expression and protein folding. Consequently, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims and claims 16-21 are rejected. Regarding claims 24-28, these claims place additional structural limitations on the peptide of claim 10, but none of these claims sufficiently reduce the sequence space because of the open-ended sequence length in each case. Because of the enormous sequence space encompassed by claims 24-28, a person of ordinary skill in the art would be required to perform undue experimentation to determine which members of the genus were G protein peptidomimetics after expression and protein folding. Consequently, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims and claims 24-28 are rejected. Regarding claim 31, claim 31 recites a method of capturing GPCR in an active conformation, the method comprising the steps of: a) bringing a G protein peptidomimetic of claim 10 into contact with a GPCR, and b) allowing the G protein peptidomimetic to bind to the GPCR, whereby the GPCR is captured in an active conformation. As described above, the activity profile of GPCRs is unpredictable, complex, and primarily described through molecular dynamics simulations. Applicant has demonstrated that cyclohexylalanine is tolerated in the last four positions of the claimed peptide, but many of the other side chains recited in Applicant Table B have a significantly larger van der Waals radius, different polarities and different numbers of free electron pairs. Some of these claimed alanine analogues possess bridging carbons, which alter the three-dimensional shape of the side chain beyond mere van der Waals radius as well. It is not clear that the entire breadth of the R9 motif would be tolerated. A person of ordinary skill in the art would be required to perform undue experimentation to test all the claimed sequence space for this recited activity. Consequently, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with this claim and claim 31 is rejected. Regarding claim 33, claim 33 recites a method of crystallizing a complex of a G protein peptidomimetic of claim 10 and a GPCR and optionally a ligand of the GPCR, the method comprising the steps of: a) providing a G protein peptidomimetic of claim 10 and a GPCR, and optionally a ligand of the GPCR, b) allowing the formation of a complex of the G protein peptidomimetic, the GPCR and optionally the ligand, and c) crystallizing the complex of step b) to form a crystal. Claim 33 requires binding activity and provides no additional enabling information. For the same reasons as claim 31 above, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with this claim and claim 31 is rejected. Regarding claim 34, claim 33 is rejected as described above. Claim 34 provides no additional enabling information. Consequently, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with this claim and claim 34 is rejected. Regarding claim 36, claim 36 recites a screening method for identifying compounds capable of interacting with a GPCR comprising a) contacting the GPCR with a test compound and a G protein peptidomimetic of claim 10; b) evaluating binding of the test compound to the GPCR; and c) optionally selecting a test compound that binds to the GPCR as a compound capable of interacting with the GPCR. Claim 36 has the same sequence space as claim 10. A person of ordinary skill in the art would be required to perform undue experimentation to screen all the claimed sequence space for this recited activity. Consequently, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with this claim and claim 36 is rejected. Regarding claim 37, claim 10 is rejected as described above. Claim 37 restricts the identities of X1a, X2a, X3a, and X4a, but it does not address X5-X10. Because of the enormous sequence space encompassed by claim 37, a person of ordinary skill in the art would be required to perform undue experimentation to determine which members of the genus were G protein peptidomimetics after expression and protein folding. Consequently, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with this claim and claim 37 is rejected. Regarding claim 38, claim 10 is rejected as described above. Claim 38 restricts the identities of X5, X6, X7, X8, and X10, but it does not address X9 or the R9 moiety. Because of the enormous sequence space encompassed by claim 38, a person of ordinary skill in the art would be required to perform undue experimentation to determine which members of the genus were G protein peptidomimetics after expression and protein folding. Consequently, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with this claim and claim 38 is rejected. Closest Prior Art Claims 10-13, 15-28, 31, 33, 34, and 36-38 are directed to a G protein peptidomimetic or salt thereof that consist of the sequences of formulae (VIII-XVII). These formulae share this common structural motif: RDX8IQRX7HLX6X5X4X3X2X1 (SEQ ID NO:8). Of significant importance is that X4X3X2X1 may not be the sequence YELL. Upon search and analysis of formula VIII and of specific sequences such as SEQ ID NOs: 150, 166, 167, 91, 175, 95, 176, 177, 99, 100, 101, 178, 114, and 116, it was concluded that the general formula VIII with the claimed negative limitation was novel and nonobvious and consequently, all formulae that include this formula. For example, Li et al. (WO2019062744, published 4/4/2019) discloses SEQ ID NO: 7, aligned against Applicant SEQ ID NO: 124 below: SQ Sequence 20 AA; Query Match 98.6%; Score 71; Length 20; Best Local Similarity 93.3%; Matches 14; Conservative 0; Mismatches 1; Indels 0; Gaps 0; Qy 1 RDIIQRMHLRQYEXL 15 ||||||||||||| | Db 6 RDIIQRMHLRQYELL 20 In this example, Applicant “X” must not be L because the neighboring residues are YE and L, and YELL is not permitted for the last four residues. Therefore, X can be I, Y, H, F, W, or an alanine analog. The prior art does not teach or suggest such a substitution at this particular location in the α5 helix C terminal region of α-subunit of the G protein-coupled receptor. As described above, the stability and activation landscape of GPCR is unpredictable and determined largely through molecular simulation. Therefore, any substitution that result in a beneficial phenotype will be difficult to predict for a person of ordinary skill in the art. Conclusion Claims 10-13, 15-22, 24-28, 31, 33, 34, and 36-38 are rejected. Claim 23 is objected to. 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 David Paul Bowles whose telephone number is (571)272-0919. The examiner can normally be reached Monday-Friday 8:30-5:00. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /DAVID PAUL BOWLES/ Examiner, Art Unit 1654 /LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654