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
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in Australia on 1/19/2021. It is noted, however, that applicant has not filed a certified copy of the AU2021900114 application as required by 37 CFR 1.55.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 9, para. 5, filed 6/3/2026, with respect to the objection to the specification regarding sequence disclosures. have been fully considered and are persuasive. Therefore, the objection has been withdrawn. However, upon further consideration, a new ground of objection is made below:
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834. The examiner has noted that the sequences recited by claims 1 and 36 are not in the sequence listing. The sequence labeled “Formula I” in the specification at para. [0015] and the sequence at para. [0131] is also not in the sequence listing.
Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2., as well as
• A statement that identifies the location of all additions, deletions, or replacements of sequence information in the “Sequence Listing XML” as required by 1.835(b)(3);
• A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4);
• A statement that the “Sequence Listing XML” includes no new matter in accordance with 1.835(b)(5); and
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
The sequences in Table 5 and paragraph [0342] lack sequence identifiers.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Previous Specification Objections
The disclosure was previously objected to because of informalities.
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 9, para. 5, filed 6/3/2026, with respect to the objection to the specification regarding sequence disclosures. have been fully considered and are persuasive. Therefore, the objection has been withdrawn. However, upon further consideration, a new ground of objection is made below:
New Specification Objections
The disclosure is objected to because of the following informalities:
The sequences in Table 5 and paragraph [0342] lack sequence identifiers. Appropriate correction is required.
Claim Status
Claims 1, 21, 23-25, 27, 31, 33-36, 56-58, 60, 61, 63, 64, 66, 67, and 71-75 filed 6/3/2026, are pending. Claims 1, 21, 23-25, 27, 31, 33-36, 56-58, 60, 61, 63, 64, 66, 67, and 71-75 are under examination.
Previous Claim Objections
Claims 1, 21, 23-25, 27, 31, 33-36, 56-58, 60, 61, 63, 64, 66, and 67 were previously objected to because of informalities.
Applicant’s arguments, see Applicant Reply, page 9, para. 5, filed 6/3/2026, with respect to the objection to the specification regarding sequence disclosures. have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of objection is made.
New Claim Objections
Claim 67 objected to because of the following informalities. The claim would read more clearly if the term “therapies” were in the singular form. For example: “The method of claim 63, wherein the method further comprises administering at least one further cancer therapy.”
Appropriate correction is required.
Previous Claim Rejections - 35 USC § 112
Claims 1, 21, 23-25, 27, 31, 33-36, 56-58, 60, 61, 63, 64, 66, and 67 were previously 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.
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 10, para. 1, filed 6/3/2026, with respect to the rejection of claims 1, 21, 23-25, 27, 31, 33-36, 56-58, 60, 61, 63, 64, 66, and 67 under 35 U.S.C. 112(b) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made.
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.
Claim 27 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.
Regarding claim 27, the phrase "such as" in line 12 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 27 is rejected.
Previous 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 63, 64, 66, and 67 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 prophylactic treatment of or decreasing likelihood of developing cancer in a subject, wherein the cancer comprises at least one PD-L1 overexpressing cell, does not reasonably provide enablement for eliminating cancer altogether wherein the cancer comprises at least one PD-L1 overexpressing cell. 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:
(A) The breadth of the claims;
The breadth of the claims center around how many cancers are involved with PD-L1 overexpression. As described below, this is a large number of cancers.
(B) The nature of the invention;
The invention is a method of treating or preventing cancer in a subject, wherein the cancer comprises at least one PD-L1 overexpressing cell, comprising administering to the subject a PD-L1 bicyclic peptide mimetic.
(C) The state of the prior art;
Cha et al. (Cha, et al. Molecular cell 76.3: 359-370 (2019)) discloses that many types of cancer are associated with PD-1 and the ligand PD-L1: “ (Cha et al., page 359, col. 1, para. 2): “In many human cancers, including renal cell carcinoma (RCC), breast cancer, colorectal cancer, gastric cancer, non-small cell lung cancer (NSCLC), papillary thyroid cancer, and testicular cancer (Thompson et al., 2004), high PD-L1 expression is detected and associated with poor prognosis (Ohaegbulam et al., 2015). Indeed, the binding between PD-L1 on cancer cells with PD-1 on tumor-infiltrating T cells (TILs) activates Src homology region 2 domain-containing phosphatases (SPH2s), leading to suppression of the T cell receptor (TCR) pathway and inhibition of T cell activity. Moreover, interruption of immune surveillance promotes cancer cell survival by exploiting PD-L1/PD-1 signaling (Schildberg et al., 2016).”
However, Tsanev (Tsanev, R. J. BUON 10: 309-318 (2005)) discloses that cancer cells may possess many different survival strategies including: 1) Reactivation of Telomerase, 2) Suppression of Apoptosis, 3) Elimination of Effector Cells, 4) Shedding of Soluble Receptors, 5) Neutralization of Tumor Suppressor Genes, 6) Development of a Detoxicating Efflux Pump, 7) Neoangiogenesis, 8) Overcoming and Utilizing Hypoxia, 9) Other Rescue Mutations, and 10) Access-Restriction Factors. (Tsanev, pages 313-315).
(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 that govern the interactions between PD-1 and PD-L1 and the other molecules in the oncogenic pathways are unpredictable in general. Regarding proteins, a single point mutation can change the biophysical properties of a protein: “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 substitutions 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).
(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.
Applicants show definitive examples of the ability of the disclosed peptides to modulate the translocation of PD-L1 and thereby influence cancer cells utilizing this pathway. However, the ability to modulate other known cancer survival strategies is not shown. Furthermore, the ability to cure, eliminate, or reduce cancer progress to zero is also not shown in any examples.
Response to Arguments
Applicant’s arguments, see , page 10, para. 1, filed 6/3/2026, with respect to the rejection of claims 63, 64, 66, and 67 under 35 U.S.C. 112(a) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made below.
The Wands analysis from above fundamentally doesn’t change.
Regarding claim 63, amended claim 63 recites: “A method of treating or preventing cancer in a subject, wherein the cancer comprises at least one PD-L1 overexpressing cell, comprising administering to the subject a PD-L1 bicyclic peptide mimetic of claim 1, wherein the preventing of cancer consists of an increase in the resistance of the subject to developing the disease or condition, or decreases the likelihood that the subject will develop the disease or condition.”
The Examiner understands the intent behind this amendment.
However, the specification at para. [0127] recites: “As used herein, the terms "treatment", "treating" and the like refer to clinical intervention designed to alter the natural course of the individual or cell being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. For example, an individual is successfully "treated" if one or more symptoms associated with a T-cell dysfunctional disorder are mitigated or eliminated, including, but are not limited to, reducing the proliferation of (or destroying) cancerous cells, reducing pathogen infection, decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, and/or prolonging survival of individuals. (Emphasis added).
The specification-defined term “treating” encompasses decreasing disease progression to zero and elimination as described above. Consequently, “treating” runs into the same enablement issue as “preventing” in the previous office action.
The data provided enables a scope including prophylactic increasing of resistance or reduction of likelihood of developed of claimed diseases. However, due to the wide breadth of cancers in which PD-L1 is involved and the wide breadth of cancer defense systems, the provided data does not support elimination of any cancer for which PD-L1 is overexpressed in at least one cell. 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 claim 63 and claim 63 is rejected.
Regarding claim 64, claim 63 is rejected as described above. Claim 64 recites the broad categories of “ cancer cell” and “cancer stem cell”. For the reasons described 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 claim 64 and claim 64 is rejected.
Regarding claim 66, claim 63 is rejected as described above. Claim 66 recites the case where the cancer is selected from breast, prostate, lung, bladder, pancreatic, colon, liver, or brain cancer, or melanoma, or retinoblastoma. These are very broad categories, and while all have PD-L1 involvement, they also include cancer types with multiple defense mechanisms. For the reasons described 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 claim 66 and claim 66 is rejected.
Regarding claims 67, claim 63 is rejected as described above. Claim 67 further recites the case wherein further comprising administering at least one further cancer therapies (e.g., a chemotherapeutic agent). Broad categories of cancers are still claimed. For the reasons described 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 claim 67 and claim 67 is rejected.
Examiner Note: Fundamentally, this enablement rejection is an issue with the definition of “treatment” as defined in the specification. Previously discussed proposed claim amendments would resolve this issue:
63. (Currently Amended) A method of ameliorating or palliating cancer in a subject, wherein the cancer comprises at least one PD-L1 overexpressing cell, comprising administering to the subject a PD-L1 bicyclic peptide mimetic of claim 1
New 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 1, 21, 24, 25, 27, 31, 33-36, 57, 58, 60, 61, 63, 64, 66, 67, and 71-75 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. This claim 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 inventors, at the time the application was filed, had possession of the claimed invention.
Regarding claim 1, the term “modified derivative” includes the following:
“In some embodiments, the modified derivative includes one or more modifications selected from: N-terminal and/or C-terminal modifications; replacement of one or more amino acid residues with one or more non-natural amino acid residues (such a replacement of one or more polar amino acids with one or more isosteric or isoelectronic amino acids; replacement or one or more hydrophobic amino acid residues with other non-natural isosteric or isoelectronic amino acids); addition of a spacer group; replacement of one or more oxidation resistant amino acid residues; replacement of one or more amino acid residues with an alanine, replacement of one or more L amino acid residues with one or more D-amino acid residues; N- alkylation of one or more amide bonds within the bicyclic peptide ligand; replacement of one or more peptide bonds with a surrogate bond; peptide backbone length modification; substitution of the hydrogen on the a-carbon of one or more amino acid residues with another chemical group, and post-synthetic biorthogonal modification of amino acids such as cysteine, lysine, glutamate and tyrosine with suitable amine, thiol, carboxylic acid and phenol-reactive reagents.” (Specification, para. [0029]).
The phrase “replacement of one more amino acid residues with an alanine” allows up to ten alanine substitutions without any clear guidance on which substitutions would still result in a PD-L1 mimetic.
The phrase “replacement of one or more L amino acid residues with one or more D-amino acid residues” does not necessarily mean replacement with the corresponding to the native L-amino acid.
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.”)
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.
Finally, Zhou et al. (Zhou, et al. Biochimica et Biophysica Acta (BBA)-Biomembranes 1858.8: 1914-1925 (2016)) discloses that peptides are also subject to significant activity changes from a single mutation: “In our study, we constructed two anticancer peptides with only one difference in residue, but they showed dissimilar modes of action. One could penetrate into cells, target on mitochondria, and induce cell apoptosis, while the other could cause cell membrane lysis. This finding provides us a good example to study the structure-function relationship of ACPs as important drugs.” (Zhou et al., Abstract).
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 13 exemplary peptides, four of which, for example, incorporate D-amino acids. Similarly, a none of these exemplary peptides demonstrate incorporation of the claimed non-natural amino acids beyond the D-amino acids.
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.
Claim 1 is rejected.
Regarding claims 21, 24, and 25, these claims do not reduce the genus size of claim 1 with respect to the modified derivatives.
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.
Claims 21, 24, and 25 are rejected.
Regarding claim 27, the phrases “replacement of one or more amino acid residues with one or more non-natural amino acid”, “replacement of one or more oxidation resistant amino acid residues”, “replacement of one or more amino acid residues with an alanine”, and “replacement of one or more L amino acid residues with one or more D-amino acid residues” create a genus of peptides which is not shown to be in the possession of the inventor.
For example, “replacement of one or more amino acid residues with one or more non-natural amino acid”, encompasses any possible non-natural amino acid, very few of which are shown in context of this peptide.
The phrase “replacement of one more amino acid residues with an alanine” allows up to ten alanine substitutions without any clear guidance on which substitutions would still result in a PD-L1 mimetic.
The phrase “replacement of one or more L amino acid residues with one or more D-amino acid residues” does not necessarily mean replacement with the corresponding to the native L-amino acid.
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.”)
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.
Finally, Zhou et al. (Zhou, et al. Biochimica et Biophysica Acta (BBA)-Biomembranes 1858.8: 1914-1925 (2016)) discloses that peptides are also subject to significant activity changes from a single mutation: “In our study, we constructed two anticancer peptides with only one difference in residue, but they showed dissimilar modes of action. One could penetrate into cells, target on mitochondria, and induce cell apoptosis, while the other could cause cell membrane lysis. This finding provides us a good example to study the structure-function relationship of ACPs as important drugs.” (Zhou et al., Abstract).
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 13 exemplary peptides, four of which, for example, incorporate D-amino acids. Similarly, a none of these exemplary peptides demonstrate incorporation of the claimed non-natural amino acids beyond the D-amino acids.
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.
Claim 27 is rejected.
Regarding claim 31, similar to claim 27, it is not necessarily the case that the D-amino acids recited by claim 31 correspond to the native L-amino acids.
Just like in the case of claim 27, 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.
Claim 31 is rejected.
Regarding claims 33-35, these claims do not reduce the genus size of claim 1 with respect to the modified derivatives.
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.
Claims 33-35 are rejected.
Regarding claim 36, this claim has the exact same genus scope as claim 1.
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.
Claim 36 is rejected.
Regarding claims 58, 60, and 61, these claims do not reduce the genus size of claim 36 with respect to the modified derivatives.
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.
Claims 58, 60, and 61 are rejected.
Regarding claim 63, this claim has the same genus size as claim 1.
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.
Claim 63 is rejected.
Regarding claims 64, 66, and 67, these claims do not reduce the genus size of claim 36 with respect to the modified derivatives.
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.
Claims 64, 66, and 67 are rejected.
Regarding claim 71, this claim has the same genus size as claim 25.
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.
Claim 71 is rejected.
Regarding claim 72, similar to claim 27, it is not necessarily the case that the D-amino acids recited by claim 72 correspond to the native L-amino acids.
Just like in the case of claim 27, 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.
Claim 72 is rejected.
Regarding claim 73, similar to claim 27, it is not necessarily the case that the D-amino acids recited by claim 73 correspond to the native L-amino acids.
Just like in the case of claim 27, 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.
Claim 73 is rejected.
Regarding claim 74, this claim has the same genus size as claim 61.
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.
Claim 74 is rejected.
Regarding claim 75, this claim has the same genus size as claim 67.
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.
Claim 75 is rejected.
Regarding claims 23 and 56, these claim are dependent upon claims 1 and 36, respectively. However, claims 23 and 56 further define the peptide sequence in such a way that it is interpreted to preclude the modified derivatives that cause a 112(a) rejection for claim 1.
Closest Prior Art
Ogawa et al. US20180113131A1, published 4/26/2018, discloses SEQ ID NO: 4:
LVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSAETGFHCVSQDGLNLLT
S
The following section of SEQ ID NO: 4: LTFIFRLRKGRMMDVKK partially matches the general formula in the case where
X1 is absent
X2 is threonine
X3 is phenylalanine
X4 is arginine
X5 is arginine
X6 is methionine
X7 is methionine
X8 is aspartic acid
X9 is lysine
X10 is lysine.
C1 and C2 are absent in SEQ ID NO: 4, which is the point of novelty.
SEQ ID NO: 4 is aligned against Applicant SEQ ID NO: 1 below for further comparison:
LENGTH: 50
TYPE: PRT
ORGANISM: Homo sapiens
Query Match 55.2%; Score 64; Length 50;
Best Local Similarity 89.5%;
Matches 17; Conservative 0; Mismatches 0; Indels 2; Gaps 2;
Qy 3 LTFIFCRLRKGRCMMDVKK 21
||||| |||||| ||||||
Db 15 LTFIF-RLRKGR-MMDVKK 31
This peptide, however, lacks the critical cysteine residues and furthermore, is not a bicyclic peptide. The prior art does not teach or suggest the insertions at these positions to result in Applicant Formula X1C1LX2X3IFC2X4LRKGX5C3X6X7X8X9KX10 or Applicant SEQ ID NO: 1.
Allowable Subject Matter
As described above, the peptide of claim 1 is novel and obvious. However, claim 1 is subject to a 112(a) rejection above.
As a result, most other claims, 21, 24, 25, 27, 31, 33-36, 57, 58, 60, 61, 63, 64, 66, 67, and 71-75, are also subject to said rejection.
Claims 23 and 56 are 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.
Conclusion
Claims 23, 56, and 67 are objected to.
Claims 1, 21, 24, 25, 27, 31, 33-36, 57, 58, 60, 61, 63, 64, 66, 67, and 71-75 are rejected.
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.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/JEANETTE M LIEB/ Primary Examiner, Art Unit 1654
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