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 .
This is the First Office Action on the Merits of US 18/650,002 filed on 04/29/2024 which is a CIP of PCT/CN2022/138732 filed on 12/13/2022 which claims foreign priority benefit of CHINA 202210689800.3 filed on 06/17/2022. An English language translation of the PCT/CN2022/138732 is not of record. An English language translation of the CHINA 202210689800.3 is NOT of record.
Claims 1-10 are pending and under examination.
Nucleotide and/or Amino Acid Sequence Disclosures: Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
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:
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). See specification para 0017; para 0033; claim 7.
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.
Claim Objections
Claims 1 and 7 are objected to because of the following informalities:
For improved clarity, amend claim 1, line 2, as follows: …administering to a patient….
Also, claim 7 should be amended to include a SEQ ID NO because the amino acid sequences in the claim lack a SEQ ID NO.
Appropriate correction is required.
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.
Claims 1-10 are rejected under 35 U.S.C. 112(b), 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.
Claim 1 recites “the peptide” in line 3. There is insufficient antecedent basis for the term “the peptide” because there is no previous “peptide” recited in the claim. The scope of the claim is unclear because while the claim recites a pharmaceutical composition comprising a polypeptide, the peptide having an amino acid sequence I or II, it is unclear if the “peptide” is the same as the “polypeptide”. For example, dependent claims 6 and 7 recite “the polypeptide” but not “the peptide”. Claims 2-10 are indefinite for the same reason as they depend from claim 1 and are not remedial.
Scope of enablement
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.
Claims 1-10 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 treating a mouse model for choroidal neovascularization (CNV) and treating diabetic retinopathy in a mouse model for chronic diabetes mellitus by administration of the peptide drug JP1-RGD (which is the instant peptide FPGSDRF-RGD), does not reasonably provide enablement for prevention of such and for treating any neovascular eye disease in a human patient as encompassed by the presently claimed invention. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized in Ex parte Forman, 230 USPQ 546 (BPAI 1986) and reiterated by the Court of Appeals in In re Wands, 8 USPQ2d 1400 at 1404 (CAFC 1988). These factors include: (1) the quantity of experimentation necessary, (2) the amount or direction presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
While all of the Wands factors are considered, a sufficient amount for a prima facie case is discussed below.
The nature of the invention: The nature of the invention is preventing or treating a neovascular eye disease in a patient by administering a therapeutic peptide of instant Formula I or II. The invention is in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The breadth of the claims: The claims encompass preventing in addition to treating. Claims 1, and 6-10 are broad to preventing & treating any neovascular eye disease. All claims except claim 7 are broad to the therapeutic peptide sequence where Z is zero and thus do not actually require the RGD integrin binding sequence.
The state of the prior art: Xie et al in “JP1, a polypeptide specifically targeting integrin aVB3, ameliorates choroidal neovascularization and diabetic retinopathy in mice” (Acta Pharmacologica Sinica Vol 44, pages 897-912; published October 24, 2022) shows the state of the prior art. Xie et al show use of JP1 peptide is successful for treating neovascular age-related macular degeneration (nAMD) and diabetic neuropathy in mice models. (See prior art rejection below.) However, Xie et al disclose that a “primate model is needed to validate” their findings and that in heterogeneous endothelial cells, JP1 may not target integrin aVB3. (See page 911, left col. Para 3).
The predictability of the art: The unpredictable nature of the broadly claimed invention is evidenced in the Xie et al reference. For example, Xie et al disclose that a “primate model is needed to validate” their findings and that in heterogeneous endothelial cells, JP1 may not target integrin aVB3. (See page 911, left col. Para 3).
The relative skill of those in the art is high, at the level of an MD OR PhD research scientist.
The amount of guidance provided in the specification is sufficient to show embodiments of treating neovascular age-related macular degeneration (nAMD) and diabetic neuropathy in mice models using the therapeutic peptide of Formula I or II having the RGD integrin targeting sequence and where the serine is phosphorylated. For example, the specification is silent regarding guidance for treating retinal vein occlusion (RVO), neovascular glaucoma, or retinopathy of prematurity (ROP).
The presence of working example: The specification shows no working example for prevention of a neovascular eye disease. Further, the specification shows no working example of treating any neovascular eye disease other than neovascular age-related macular degeneration (nAMD) and diabetic neuropathy in mice models using the therapeutic peptide of Formula I or II having the RGD integrin targeting sequence and where the serine is phosphorylated.
The quantity of experimentation necessary is complex and unpredictable as evidenced by the instant specification and state of the prior art. For example, it is unknown if the presently claimed invention would in fact be able to prevent neovascular diseases in a human patient.
As such, the art of the claimed invention lacks predictability because the claims are drawn too broadly. As a result, the effect of performing the invention by one skilled in the art would be that of undue experimentation.
Claim Rejections - 35 USC § 102
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4, and 7-10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Xie et al in “JP1, a polypeptide specifically targeting integrin aVB3, ameliorates choroidal neovascularization and diabetic retinopathy in mice” (Acta Pharmacologica Sinica Vol 44, pages 897-912; published October 24, 2022) as evidenced by Cui et al “JP1 suppresses proliferation and metastasis of melanoma through MEK1/2 mediated NEDD4L-SP1-Integrin αvβ3 signaling. (Theranostics, 2020 Vol 10, No. 18, July 1, 2020).
Regarding claim 1, Xie et al discloses a method for treating a neovascular eye disease comprising administering a patient in need thereof a pharmaceutical composition comprising the JP1 therapeutic peptide. (See Title; Abstract; entire article.) As evidenced by Cui et al, the JP1 therapeutic peptide of Xie et al is the peptide having an amino acid sequence FPGSDRF-Z; wherein: S represents phosphorylated serine; and Z is -RGD. (See Cui et al; abstract, page 2, right col., para 3; Fig1, sections A-M).
Regarding claim 2, Xie et al disclose the neovascular eye disease wet macular degeneration. Absent evidence to the contrary, wet macular degeneration is construed as being encompassed by/the same as neovascular age-related macular degeneration (nAMD) (See Abstract, entire article.)
Regarding claim 3, Xie et al disclose the neovascular age-related macular degeneration (nAMD). (See Abstract, entire article.)
Regarding claim 4 Xie et al disclose the neovascular eye disease diabetic retinopathy (DR). (See Abstract, entire article.)
Regarding claim 7, Xie et al disclose the polypeptide has an amino acid sequence of JP1 which is the FPGSDRF-RGD having the serine (S) of the amino acid sequence of FPGSDRF-RGD being phosphorylated. (See page 911, right col. Para 2). As evidenced by Cui et al, the JP1 therapeutic peptide of Xie et al is the peptide having an amino acid sequence FPGSDRF-Z; wherein: S represents phosphorylated serine; and Z is -RGD. (See Cui et al; abstract, page 2, right col., para 3; Fig1, sections A-M).
Regarding claim 8, Xie et al disclose the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. (See Abstract, entire article.)
Regarding claim 9, Xie et al disclose the pharmaceutical composition is for intraocular injection or eye drops, specifically intravitreal injection (IVT). (See Abstract, entire article.)
Regarding claim 10, Xie et al disclose the pharmaceutical composition is for extraocular administration. Xie et al disclose intraperitoneal injection of JP1 (e.g., page 908, FIG 7 legend; page 904, right col., para 5). Note that extraocular administration is construed as acting outside the eye, such as systemic medications, injections into other parts of the body, or therapies targeting structures outside the ocular cavity).
Thus, Xie et al as evidenced by Cui et al anticipates claims 1-4, and 7-10.
Claim Rejections - 35 USC § 103
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.
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4, and 6-10 are rejected under 35 U.S.C. 103 as being unpatentable over Cui et al “JP1 suppresses proliferation and metastasis of melanoma through MEK1/2 mediated NEDD4L-SP1-Integrin αvβ3 signaling. (Theranostics, 2020 Vol 10, No. 18, July 1, 2020), in view of Zhou et al (US2016/0068570), in view of Inge Van Hove et al “Targeting RGD-binding integrins as an integrative therapy for diabetic retinopathy and neovascular age-related macular degeneration” (Progress in Retinal and Eye Research, 2021 Vol 85, 11/30/2021), in view of Boyer et al in “Safety and Efficacy of Intravitreal Risuteganib for Non-Exudative AMD: A Multicenter, Phase 2a, Randomized, Clinical Trial” Clinical Science June 1, 2021).
Regarding claim 1, Cui et al discloses a method of treating melanoma in a mouse model subject by administration of the peptide JP1. Cui et al disclose that the peptide JP1 has a therapeutic effect on proliferation and metastasis of melanoma by means of a NEDD4L-SP1-integrin αvβ3. JP1 suppresses proliferation and metastasis of melanoma through MEK1/2 mediated NEDD4L-SP1-Integrin 3 signaling pathway. Cui et al disclose that the JP1 is FPGSDRF-RGD having a phosphorylated serine (See abstract, page 2, right col., para 3; Fig1, sections A-M).
Further, regarding claim 1, Zhou et al (US2016/0068570) discloses a polypeptide comprising the amino acid sequence FPGSDRF-Z, the amino acid S being phosphorylated. Further, the Z element is (G)n-RGD where n may be zero. Zhou et al points out that the effect of the JWA gene on various malignant phenotypes related to tumor cell metastasis is achieved by negatively regulating the expression of the nuclear transcription factor Sp1 and then further inhibiting the activity of integrin aVB3 signal pathway molecules (See Abstract; ref claims 1-5; para 4). For example, Zhou et al recites in the Abstract:
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However, Cui et al and Zhou et al differ from instant claim 1 in that the use of the polypeptide is different.
Inge Van Hove et al disclose targeting RGD-binding integrins as an integrative therapy for diabetic retinopathy and neovascular age-related macular degeneration” (See abstract; Table 2). Inge Van Hove et al reviews the pathophysiological role of RGD binding integrins in complex multifactorial retinal disorders, and points out that various RGD integrin receptor antagonists achieve the effects of reducing leakage, angiogenesis, fibrosis, and inflammation by binding to Integrin alpha vBeta3. (See Abstract; table 2).
Boyer et al disclose a clinical trial for treating nonexudative (dry) AMD. Patients were administered therapeutic peptide risuteganib by intravitreal injection. Risuteganib is a small peptide integrin regulator that has been shown to protect human RPE cells against OS-associated cellular dysfunction.
Regarding claim 2, Inge Van Hove et al disclose the neovascular eye disease nAMD which is construed to meet the limitation of wet macular degeneration (See abstract; Table 2).
Regarding claim 3, Inge Van Hove et al disclose the neovascular age-related macular degeneration (nAMD). (See abstract; Table 2).
Regarding claim 4 Inge Van Hove et al disclose the neovascular eye disease diabetic retinopathy (DR). (See abstract; Table 2).
Regarding claim 6, Zhou et al disclose the polypeptide comprises an acetylated N-terminal (N-terminal acetylation involves transfer of an acetyl group (-COCH3) from acetyl-CoA to the a-amino group of the first amino acid in a protein) and an amidated C-terminal (a peptide whose C-terminus is modified so that its terminal (-COOH) is replaced by a carboxamide (-CONH2). Zhou et al disclose that these features are used for therapeutic peptides to mimic natural peptides and improve activity, stability, and bioavailability. An “amidated C-terminal” means the peptide’s last amino acid’s carboxyl group has been converted to a carboxamide, a modification that neutralizes the terminal charge, enhances stability, and often boosts biological activity. (See para 0018; 0068; 0076; 0091; 0099; ref claims 3 and 7.)
Regarding claim 7, both Cui et al and Zhou et al disclose the polypeptide has an amino acid sequence of FPGSDRF-RGD, and serine (S) of the amino acid sequence of FPGSDRF-RGD is phosphorylated. (See Cui et al page 8037, right col. “Results”.)
Regarding claim 8, Cui et al, Inge Van Hove et al, and Boyer et al disclose the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
Regarding claim 9, Cui et al, Inge Van Hove et al, and Boyer et al disclose the pharmaceutical composition is for intraocular injection or eye drops. (See abstracts, entire articles.)
Regarding claim 10, Cui et al disclose the pharmaceutical composition is for extraocular administration. (i.e., treatments that act outside the eye, such as systemic medications, injections into other parts of the body, or therapies targeting structures outside the ocular cavity). (See page 8038, right col., last para, citing tail-vein injection).
The level of skill in the art was high before the effective filing date of the presently claimed invention.
One of ordinary skill in the art would have been motivated to use a pharmaceutical composition comprising the therapeutic SP1 peptide of Cui et al and Zhou et al for the use of treating a patient for wet AMD or diabetic neuropathy, for the rationale of Inge Van Hove et al who disclose targeting RGD-binding integrins as an integrative therapy for diabetic retinopathy and neovascular age-related macular degeneration” (See abstract; Table 2). Inge Van Hove et al reviews the pathophysiological role of RGD binding integrins in complex multifactorial retinal disorders, and points out that various RGD integrin receptor antagonists achieve the effects of reducing leakage, angiogenesis, fibrosis, and inflammation by binding to Integrin alpha vBeta3. (See Abstract; table 2).
In view of the high skill level in the art, it would have been obvious to one of ordinary skill in the art to combine the elements of the cited references, using an integrin receptor agonist SP1 of Cui et al and Zhou et al for the rationale of treating a subject with a neovascular eye disease being a diabetic retinopathy and neovascular age-related macular degeneration because Cui et al shows this drug was available and Van Hove et al disclose targeting RGD-binding integrins as an integrative therapy for diabetic retinopathy and neovascular age-related macular degeneration” (See abstract; Table 2).
Absent evidence to the contrary, it is considered that one of ordinary skill in the art having the cited references before the effective filing date of the presently claimed invention would have had a reasonable expectation of success to combine the SP1 drug of Cui et al and Zhou et al for treating diabetic retinopathy and neovascular age-related macular degeneration to arrive at the presently claimed invention.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE S HIBBERT whose telephone number is (571)270-3053. The examiner can normally be reached M-F 8:00-5:00.
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/CATHERINE S HIBBERT/Primary Examiner, Art Unit 1658
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