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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8/25/2026 has been entered.
Objections/Rejections Withdrawn
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied, and constitute the complete set presently being applied to the instant application.
Response to Arguments
Applicant's arguments, see Pg 5, filed 8/25/2026 in response to rejection of claims 21 and 22 under 35 U.S.C. 112(d) have been fully considered but they are not persuasive.
Applicant’s position is that SEQ ID NO: 87 is a cyclized peptide. However, not including the cyclization of the peptide, SEQ ID NO: 87 exhibits the following amino acid alterations relative to SEQ ID NO: 1:
SEQ ID NO: 1 - WKDEAGKPLVK
SEQ ID NO: 87 – wKEe*CGKP*LVk [Wingdings font/0xE0] six total differences, where lowercase letters are D-amino acids and * indicates Glu(Me) or Pro(Me)
Because the total number of amino acid alterations relative to SEQ ID NO: 1 is greater than 3, as recited in claim 1, the rejection under 35 U.S.C. 112(d) has been modified/maintained herein.
Applicant’s arguments, see Pg 6, filed 8/25/2026, with respect to the rejection(s) of claim(s) under 35 U.S.C. 102(a)(1) and 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amended claims.
Claim Status
Claims 1, 14, 15, 18, 19, 21-25, and 32 are pending under examination. Claims 2-13, 16-17, 20, and 26-31 are cancelled. Claims 1 and 21 are currently amended.
Priority
The Application is the 371 national stage entry of PCT/EP2021/052939, filed 2/8/2021, which claims priority to EP20156088.5, filed 2/7/2020. The priority date of 2/7/2020 is acknowledged.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," 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 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) 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") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) 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 of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
1. Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
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.
See Pg 3, lines 6 and 9
2. Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
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 incorporation-by-reference paragraph, 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.
The latest CRFE on file is entitled “17795331_3_1.txt” from 2-1-2023 with a byte size of 23973. Please update the incorporation by reference statement to reflect this latest filing.
Specification
The disclosure is objected to because of the following informalities: On Pg 12, the peptide fragment “LVK” lists two SEQ ID NO’s next to it – SEQ ID NO: 20 and SEQ ID NO: 82. It is presumed that the peptide fragment “LVK” is SEQ ID NO: 82.
Appropriate correction is required.
Claim Objections
Claim 1 is objected to because of the following informalities: The claim recites treating both cardiomyocyte fibrosis and myocardium fibrosis as well as renal and kidney fibrosis. The recitation of cardiomyocytes and myocardium is redundant because cardiomyocytes make up the myocardium. The recitation of renal and kidney is also redundant because renal and kidney refer to the same organ. For each pair of duplicates, amend the claim to recite one or the other but not both.
Claim 21 is objected to because in line 2 “and” is recited twice between SEQ ID NO: 73 and SEQ ID NO: 86.
Appropriate correction is required.
Claim Interpretation
Claim 1 recites a method of treating a disease or condition associated with an increase in PANX1 signaling or expression, wherein the disease or condition is selected from inflammation caused by injury. The limitation “inflammation caused by injury” is being interpreted as any injury to any part of a subject that results in inflammation.
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.
First rejection – new matter
Claim 21 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant specification provides support for a method of treating a disease or condition associated with an increase in PANX1 signaling or expression comprising administering SEQ ID NO: 1 or a variant thereof. However, SEQ ID NO: 88 and 89 are full-length isoforms of PANX1 rather than variants of SEQ ID NO: 1 (see instant Pg 7, lines 12-29), and administering them in a method of treatment is not supported by the originally filed application.
This is a new matter rejection.
Second rejection – scope of enablement for prevention
Claims 1, 14, 15, 18, 19, 21-25 and 32 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 disease or condition associated with an increase in PANX1 signaling or expression, does not reasonably provide enablement for preventing a disease or condition associated with an increase in PANX1 signaling or expression. 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.
The Applicant’s attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
1) Nature of the invention and 5) breadth of the claims: The claims are drawn to a
method for the treatment of a disease or condition associated with an increase in PANX1 signaling or expression in a subject, wherein the disease is selected from hepatic, renal, cardiomyocyte, bone marrow, kidney, or skin fibrosis or inflammation caused by injury, the method comprising administering SEQ ID NO: 1 or a variant thereof. The instant specification defines treatment as 1) referring to an intervention (e.g., the administration of an agent to a subject) which cures, ameliorates or lessens the symptoms of a disease or removes (or lessens the impact of) its cause(s), synonymous with “therapy,” or, alternatively, 2) referring to an intervention (e.g. the administration of an agent to a subject) which prevents or delays the onset or progression or a disease or reduces (or eradicates) its incidence within a treated population, synonymous with “prophylaxis” (Pg 13, lines 24-34). The alternative definition of “treatment” reads on prevention; thus, the claims are effectively drawn to administering SEQ ID NO: 1 or a variant thereof to any individual with or without an increased PANX1 signaling or expression, as prevention does not require a subject in need to already have such a condition.
2) State of the prior art and 4) predictability or unpredictability of the art: At the time of filing, it was known in the art that certain PANX1-associated diseases or conditions could be treated with peptide therapeutics or small molecule compounds but reports describing a preventative effect conferred by the same therapeutics were lacking (Penuela S, Harland L, Simek J, Laird DW. Pannexin channels and their links to human disease. Biochem J. 2014 Aug 1;461(3):371-81.).
Penuela et al. teach that PANX1 signaling alterations contributed to a variety of diseases and/or conditions, including cancer (glioma, human basal and squamous cell carcinoma, and melanoma), ischemia and stroke, seizures, glaucoma, colitis and Crohn’s disease, neurotoxicity, multiple sclerosis and encephalomyelitis, migraines and hypertension, and infectious disease. Of these, only ischemia and stroke, seizures, and certain microorganism-driven infections were treated with PANX1 therapeutics or therapeutics that target PANX1 and other channel receptors in certain experimental conditions, and only after the onset of the disease or condition (Pg 374-379).
Additionally, another study by Weilinger et al. evaluated the ability of a therapeutic peptide to prevent neural death during ischemic stroke (Weilinger NL, Tang PL, Thompson RJ. Anoxia-induced NMDA receptor activation opens pannexin channels via Src family kinases. J Neurosci. 2012 Sep 5;32(36):12579-88.). Weilinger demonstrated through whole-cell recordings that pharmacological inhibition or conditional genetic deletion of Panx1 strongly attenuated the anoxic depolarization of CA1 pyramidal neurons in acute brain slices from rats and mice. Weilinger also tested the therapeutic peptides TAT-Panx1305-318, which interferes with the SFK-interacting domain of PANX1 in the C-terminus of the protein; 10Panx; the SFK inhibitor PP2; and an anti-Panx1 antibody (α-panx1). Weilinger notes that, in experiments where drugs were included in the pipette solution, a minimum of 10 minutes was allowed for intracellular equilibration, thus exposing the brain slices to the drugs prior to initiation of anoxia to stimulate or mimic ischemia (Pg 12580, bottom paragraph of first column through top paragraph of second column). In other words, Weilinger simulated prevention through the introduction of drugs to the brain slices prior to the onset of anoxia.
Figure 1 shows whole cell recordings from CA1 pyramidal neurons in hippocampal slices exposed to anoxia (onset indicated by arrows) with and without the presence of 10Panx and α-panx1. Similarly, Figure 5 shows traces of the anoxic depolarization wherein the TAT peptide is compared to TAT-Panx1305-318. In both figures, the data demonstrate a reduction in the amplitude of depolarization and faster recovery to the baseline with the presence of PANX1 therapeutics. However, none of the therapeutics administered to the brain slices prior to initiation of anoxia could completely stop or inhibit depolarization and the subsequent restoration of the baseline. Thus, where prevention is defined as to stop something from occurring completely, the art at the time indicated a lack of support for the prevention of PANX1-associated diseases and/or conditions.
Based on these teachings, one skilled in the art would reasonably predict that diseases or conditions associated with increased PANX-1 signaling or expression could not be prevented.
3) The relative skill of those in the art: The relative skill of those in the art is high.
6) The amount of direction or guidance presented: At the time of filing, no direction or
guidance was presented in either the prior art or the instant specification that would enable one to administer SEQ ID NO: 1 or a variant thereof to prevent a PANX1 associated disease or condition as claimed.
7) The presence or absence of working examples: The instant specification provides
no examples wherein SEQ ID NO: 1 or a variant thereof is administered prior to the onset of a PANX-1 associated disease or condition in attempt to prevent said disease or condition.
8) The quantity of experimentation necessary: As there are no working examples in
either the instant specification or the prior art, reasonable guidance with respect to preventing a disease or condition associated with increased PANX1 signaling or expression through administration of SEQ ID NO: 1 or a variant thereof was limited. Consequently, one skilled in the art would be burdened with undue experimentation to determine the precise parameters and conditions necessary to effectively prevent a disease or condition associated with increased Panx1 signaling or expression.
Therefore, in view of the Wands factors, as discussed above, Applicants fail to provide sufficient information to practice the claimed invention.
Third rejection – scope of enablement for SEQ ID NO: 88 and 89
Claim 21 is 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 disease or condition associated with an increase in PANX1 signaling or expression with SEQ ID NO: 1 or a variant thereof, does not reasonably provide enablement for preventing a disease or condition associated with an increase in PANX1 signaling or expression with SEQ ID NO: 88 or 89. 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.
The Applicant’s attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
1) Nature of the invention and 5) breadth of the claims: The claims are drawn to a
method for the treatment of a disease or condition associated with an increase in PANX1 signaling or expression in a subject, wherein the disease is selected from hepatic, renal, cardiomyocyte, bone marrow, kidney, or skin fibrosis or inflammation caused by injury, the method comprising administering SEQ ID NO: 1 or a variant thereof, wherein the variant is selected from SEQ ID NO: 2-65, 68, 73, and 86-90.
2) State of the prior art and 4) predictability or unpredictability of the art: At the time of filing, SEQ ID NO: 88 and 89 were recognized full-length isoforms of PANX1 (see instant Pg 7, lines 12-29). In multiple in vitro studies conducted by others, overexpression of full-length PANX1 leads to channel activation (see, for instance, Pg 5074, right column, “Panx1 is a non-selective hemichannel when overexpressed in mammalian cells” and Figure 3 of Pelegrin et al., Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. EMBO J. 2006 Nov 1;25(21):5071-82.; and Pg 3, second paragraph, Pg 4, first paragraph, and Figures 2-3 of Chekeni et al. Pannexin 1 channels mediate 'find-me' signal release and membrane permeability during apoptosis. Nature. 2010 Oct 14;467(7317):863-7.).
Based on these teachings, one skilled in the art would reasonably predict that administering a full-length isoform of PANX1 to a subject wherein the subject has increased expression or signaling of PANX1 would lead to further PANX1 activity rather than successful treatment of said increased activity and/or expression.
3) The relative skill of those in the art: The relative skill of those in the art is high.
6) The amount of direction or guidance presented: At the time of filing, no direction or
guidance was presented in either the prior art or the instant specification that would enable one to administer SEQ ID NO: 88 or 89 to treat a PANX-1 associated disease or condition as claimed.
7) The presence or absence of working examples: The instant specification provides
no examples wherein SEQ ID NO: 88 or 89 is administered to treat diseases or conditions associated with PANX1 increased signaling or expression.
8) The quantity of experimentation necessary: As there are no working examples in
either the instant specification or the prior art, reasonable guidance with respect to treating a disease or condition associated with increased PAXN1 signaling or expression through administration of SEQ ID NO: 88 or 809 was limited. Consequently, one skilled in the art would be burdened with undue experimentation to determine the precise parameters and conditions necessary to effectively treat said diseases or conditions via administration of SEQ ID NO: 88 or 89.
Therefore, in view of the Wands factors, as discussed above, Applicants fail to provide sufficient information to practice the claimed invention.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 21 and 22 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 21 and 22 recite that the peptide is selected from SEQ ID NO: 2-65, 68, 73 and 86-90 or SEQ ID NO: 86 and 87, respectively. SEQ ID NO: 74-87 all have more than 3 alterations relative to SEQ ID NO: 1.
Regarding claim 21, SEQ ID NO: 74-85 are peptide fragments ranging in length from 3-5 amino acids in length; because SEQ ID NO: 1 is 11 amino acids in length, there are at least 6-8 amino acid that differ between SEQ ID NO: 1 and any one of SEQ ID NO: 74-85.
Additionally, SEQ ID NO: 88 and 89 each recite a full-length isoform of PANX1, which is hundreds of amino acids in length.
Regarding claim 22, SEQ ID NO: 86 and 87 display the following differences relative to SEQ ID NO: 1:
SEQ ID NO: 1 - WKDEAGKPLVK
SEQ ID NO: 86 – wkDEaGKPLvk [Wingdings font/0xE0] five total differences
SEQ ID NO: 87 – wKEe*CGKP*LVk [Wingdings font/0xE0] six total differences, where lowercase letters are D-amino acids and * indicates Glu(Me) or Pro(Me)
Therefore, these claims do not recite all the limitations of their parent claim, claim 1, because each variant claimed has more than the recited 3 amino acid alterations.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
First rejection
Claim(s) 1, 14, 15, 18, 21, 23-25 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over EP-3329930-A1 (EP ‘930, published 6/6/2018) in view of Yanguas et al. (Genetic ablation of pannexin1 counteracts liver fibrosis in a chemical, but not in a surgical mouse model. Arch Toxicol. 2018 Aug;92(8):2607-2627.).
EP ‘930 teaches a pharmaceutical composition comprising a pharmaceutically effective amount of a peptide comprising an amino acid sequence of SEQUENCE ID NO. 1 or a variant thereof. Uses of the pharmaceutical composition in the treatment of metabolic disorders, diseases characterized by muscle wasting or reduced protein synthesis, and diseases mediated by oxidative stress, are also disclosed (Abstract).
Regarding claim 1, SEQUENCE ID NO. 1 of EP ‘930 and the instant SEQ ID NO: 1 are identical (Sequence Listing). EP ‘930 teaches the peptide has up to 50 amino acids in length ([0018, 0019, 0066]).
EP ‘930 teaches that a “variant” of the peptide shall be taken to mean a peptide having an amino acid sequence that is substantially identical to SEQUENCE ID NO. 1, but which is altered in respect of one or more amino acid residues. Preferably such alterations involve the insertion, addition, deletion and/or substitution of 11 or fewer amino acids, more preferably of 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, preferably 5 or fewer, 4 or fewer, even more preferably 3 or fewer, most preferably of 1 or 2 amino acids only ([0067]).
EP ‘930 further teaches the peptide SEQUENCE ID NO. 1 and variants thereof can be used in methods of treatment of a variety of diseases and conditions including skin conditions such as scars ([0119]), wound healing ([0032, 0120]), and a disease or condition characterized by damaged epithelial or dermal cells or tissues ([0029, 0074]).
EP ‘930 does not expressly teach that any of the above diseases or conditions are associated with increased PANX1 signaling or expression.
Yanguas teaches liver fibrosis is a wound healing response to chronic injury characterized by excessive extracellular matrix deposition. At the cellular level, the main contributors to the fibrotic response are activated hepatic stellate cells (HSCs). This activation program is a complex cellular signaling process in which HSCs interact with hepatocytes, sinusoidal endothelial cells, Kupffer cells and infiltrating immune cells. Immune cells participate in the promotion of hepatocellular damage, the activation and survival of HSCs and fibrosis regression. Indeed, blockage of macrophage infiltration inhibits HSC activation and attenuates fibrotic responses. The mechanisms driving cellular attraction mainly involve paracrine communication circuits, including adenosine-5’ triphosphate (ATP) signaling. Upon injury, apoptotic cells release ATP and uridine-5’ triphosphate into the extracellular milieu via pannexin1 (Panx1), which act as “find-me” signals to attract monocytes, macrophages and microglia to the area of the insult.
Panx channels have been recently identified as critical mediators in ATP release. The Panx family consists of 3 members, called Panx1-3, with the former being the most widespread isoform. In the liver, Panx1 was reported to be expressed by hepatocytes, Kupffer cells and HSCs. In addition to playing a role in physiological conditions, Panx1 channels underlie cell death and inflammatory processes. The latter involves the activation of the Nalp3 inflammasome complex and initiation of leukocyte migration. In fact, in cardiac fibrosis, cardiomyocytes release ATP through Panx1 channels leading to early fibroblast activation and subsequent expression of IL1β. This supports the notion that extracellular ATP participates in myofibroblast activation pathways, which in turn trigger immune-related responses (Pg 2-3, “Introduction).
Yanguas further teaches a number of reports have described upregulated Panx1 expression levels as a consequence of liver disease, and RT-qPCR analysis demonstrated increased Panx1 RNA expression levels were increased in response administration of CCl4 and BLD to mice, which are designed to experimentally induce liver fibrosis (Pg 6, “3.1 Panx1 expression in liver fibrosis”; Figure 1). Additionally, Yanguas teaches CCl4-treated Panx1-/- treated mice displayed fewer signs of livery injury and fibrosis (Pg 6, “3.2 Effects of genetic Panx1 deficiency on hepatocellular injury and liver fibrosis”; Figure 2b; Pg 9, “4 Discussion,” first paragraph).
In summary, EP ‘930 teaches administration of SEQ ID NO: 1 to treat diseases and conditions such as those characterized by damaged epithelial or dermal cells or tissues and wound healing. Yanguas teaches liver fibrosis is a wound healing response to chronic injury characterized by excessive extracellular matrix deposition, further characterized by inflammation that is in part mediated by the release of ATP through PANX1.
Based on these teachings, it would be obvious to administer SEQ ID NO: 1 to treat liver inflammation caused by injury as well as liver fibrosis. One skilled in the art would be motivated to do so because EP ‘930 teaches SEQ ID NO: 1 can treat diseases or conditions characterized by epithelial or dermal damage to cells or tissues and would healing, which are involved in the progression of liver fibrosis (from initial or sustained injury and inflammation to fibrosis). One would have a reasonable expectation of success because Yanguas demonstrated that Panx1 is upregulated in the liver in response to injury and inflammation and genetic deletion, or suppression, of it protects the liver from injury, inflammation, and fibrosis; therefore, one skilled in the art would recognize that administering a therapeutic peptide that can inhibit PANX1 would similarly be able to treat livery injury, inflammation, and fibrosis.
Regarding claim 14, as stated above, EP ‘930 teaches SEQ ID NO: 1 (Sequence Listing).
Regarding claim 15, as stated above, EP ‘930 teaches that a “variant” of the peptide shall be taken to mean a peptide having an amino acid sequence that is substantially identical to SEQUENCE ID NO. 1, but which is altered in respect of one or more amino acid residues, preferably 3 or fewer amino acids ([0067]).
Regarding claim 18, EP ‘930 teaches that peptide structure modifications can include the generation of retro-inverso peptides comprising the reversed sequence encoded by D-amino acids ([0066], [0132], [0160]).
Regarding claim 21, EP ‘930 teaches that therapeutically effective variants of the peptide SEQUENCE ID NO. 1 include the peptides SEQ ID NO: 2-65, 68, and 73, which are identical to the instant SEQ ID NO: 2-65, 68, and 73, respectively ([0097]-[0102]); Sequence Listing starting on Pg 33). SEQUENCE ID NO. 1 of EP ‘930 also reads on the instant SEQ ID NO: 90.
Regarding claims 23-25, EP ‘930 teaches that the peptides taught can be chemically modified to increase their stability. The modifications can include, but are not limited to, modifications to side chains, incorporation of unnatural amino acids and/or their derivatives during peptide synthesis and the use of cross-linkers and other methods that impose conformational constraint on the peptides or their analogs ([0066], with detailed examples provided starting on line 24). Other types of modifications taught by EP ‘930 include conjugating the peptide with a binding partner, cyclisation, addition of N- or C-terminal, or side chain, protecting groups, replacing L-amino acids with D-isomers, amino acid modification, increased plasma protein binding, increased albumin binding ([0132]-[0156], [0163], [0165], [0167]-[0184]).
Regarding claim 32, as stated above, EP ‘930 teaches a peptide having up to 50 amino acids in length and comprising SEQ ID NO: 1 ([0018, 0019, 0066]; Sequence Listing).
Claim(s) 1, 14, 15, 18, 19, 21-25 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over EP-3329930-A1 (EP ‘930, published 6/6/2018) and Yanguas et al. (Genetic ablation of pannexin1 counteracts liver fibrosis in a chemical, but not in a surgical mouse model. Arch Toxicol. 2018 Aug;92(8):2607-2627.), as applied to claims 1, 9, 14, 15, 18, 21, 25 and 28-32, and further in view of Khaldi et al. (WO-2021078912-A1, effectively filed 10/22/2019), as evidenced by Heyens et al. (Liver Fibrosis in Non-alcoholic Fatty Liver Disease: From Liver Biopsy to Non-invasive Biomarkers in Diagnosis and Treatment. Front Med (Lausanne). 2021 Apr 14;8:615978.).
The teachings of EP ‘930 and Yanguas have been set forth above. EP ‘930 and Yanguas do not teach administering a variant of SEQ ID NO: 1 wherein at least two residues selected from residues 1, 2, 5, 10, and 11 are substituted with the D-form of the amino acid.
Khaldi teaches treating non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) with the peptide SEQUENCE ID NO: 1 (WKDEAGKPLVK) or a variant thereof (Abstract). SEQUENCE ID NO: 1 of Khaldi is identical to the instant SEQ ID NO: 1. Khaldi further teaches the variant SEQUENCE ID NO. 2, wherein the residues at positions 1, 2, 5, 10 and 11 are provided as D-amino acids, as compared to SEQ ID NO. 1 (Pg 2, lines 1-6).
As evidenced by Heyens, NAFLD comprises different stadia going from isolated steatosis to non-alcoholic steatohepatitis (NASH). NASH is a chronic state of liver inflammation that leads to the transformation of hepatic stellate cells to myofibroblasts. These cells produce extra-cellular matrix that results in liver fibrosis (Title; Abstract; Figure 1).
In summary, EP ‘930 and Yanguas teach a method of treating a disease or condition associated with increased PANX1 signaling or expression in a subject, wherein the disease is hepatic fibrosis or inflammation caused by injury to the liver. Khaldi teaches a method of treating NAFLD or NASH, which is a chronic state of liver inflammation that leads to hepatic fibrosis.
Based on these teachings, it would be prima facie obvious to treat hepatic inflammation caused by injury and the ensuing hepatic fibrosis with SEQ ID NO: 2 of Khaldi. One skilled in the art would be motivated to do so because Yanguas taught that PANX1 contributes to the progression of liver injury, inflammation, and fibrosis and Khaldi taught that NAFLD and NASH are species of liver injury, inflammation, and fibrosis. One would have a reasonable expectation of success as EP ‘930 and Yanguas teach that it is obvious to treat liver injury, inflammation, and fibrosis with SEQ ID NO: 1, from which SEQ ID NO: 2 is derived.
Regarding claims 21 and 22, Khaldi teaches the peptides 1) SEQUENCE ID NO. 2, which is identical to the instant SEQ ID NO: 86 and 2) SEQUENCE ID NO: 3, which is identical to the instant SEQ ID NO: 87 (Pg 2, lines 1-10 and 35-51; claims 12 and 15).
Second rejection
Claim(s) 1, 14, 15, 18, 21, 23-25 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over EP-3329930-A1 (EP ‘930, published 6/6/2018) in view of Dolmatova et al. (Cardiomyocyte ATP release through pannexin 1 aids in early fibroblast activation. Am J Physiol Heart Circ Physiol 303: H1208-H1218, 2012).
The teachings of EP ‘930 have been set forth above. Regarding claim 1, EP ‘930 does not teach administering SEQ ID NO: 1 to treat cardiomyocyte or myocardium fibrosis associated with increased PANX1 signaling or expression.
Dolmatova teaches fibrosis following myocardial infarction is associated with increases in arrhythmias and sudden cardiac death. Initial steps in the development of fibrosis are not clear; however, it is likely that cardiac fibroblasts play an important role. In immune cells, ATP release from pannexin1 (Panx1) channels acts as a paracrine signal initiating activation of innate immunity. ATP has been shown in noncardiac systems to initiate fibroblast activation. Therefore, it was postulated that ATP release through Panx1 channels and subsequent fibroblast activation in the heart drives the development of fibrosis in the heart following myocardial infarction.
Cardiac ischemia causes cells in the infarcted region to die, whereas cells in surrounding regions survive with altered electrical and biochemical properties. In these areas, activation of surviving fibroblasts leads to increases in cytokines, chemokines, extracellular matrix deposition, and fibrosis, which separates myocyte bundles, isolating surviving cells from the remaining myocyte syncytium. This heterogeneity of substrate leads to slowed cardiac conduction and formation of arrhythmias. Panx1 channels in intact heart directly interact with the scaffolding protein SAP97 through the proximal end of the Panx1 C-terminus in the region spanned by amino acids 300 –357 and the SH3-Hook domain and the proximal end of the inactive GUK domain of SAP97 (amino acid 569 –764). Ischemia increases this interaction at myocyte (cardiomyocyte) cellular membranes very early following cellular injury. Increased membrane channel density following cellular stress and increased Panx1 function via caspase activation led to ATP release into the extracellular space at levels high enough to impact cells over a distance. Additionally, ATP stimulation of fibroblasts caused rapid transformation to the myofibroblast phenotype and activates many profibrotic signaling pathways. Together, these data suggest that early in ischemia Panx1 channels may provide a paracrine signal which initiates fibroblast activation, leading to fibrosis and formation of a heterogeneous substrate in the post-myocardial infarction heart.
Purinergic (ATP) receptors are found in abundance in the heart, including ionotropic P2X receptors that have been linked to signal transduction in cellular injury. ATP activation of P2X receptors has been linked with inflammation, IL-1production, and MAPK pathway activation in other systems. A gene array analysis of ATP-activated fibroblasts suggests that these cellular events are occurring here as well. It is interesting to note that one of the highest fold change in gene expression in ATP-activated fibroblasts is in IL-1 (Table 2), suggesting that ATP signaling is involved in fibroblasts involvement in the immune response (Pg H1214, left column, “Discussion”).
In summary, EP ‘930 teaches administration of SEQ ID NO: 1 to treat diseases and conditions such as those characterized by damaged epithelial or dermal cells or tissues and wound healing. Dolmatova teaches the increased activity of Panx1 in cardiomyocytes contributes to the initiation of cardiomyocyte fibrosis in response to myocardial infarction injury and inflammation.
Based on these teachings, it would be obvious to administer SEQ ID NO: 1 to treat cardiomyocyte inflammation in response to injury and subsequent fibrosis. One skilled in the art would be motivated to do so because EP ‘930 teaches SEQ ID NO: 1 can treat diseases or conditions characterized by epithelial or dermal damage to cells or tissues and would healing, which are processes involved in the development of cardiomyocyte fibrosis in response to myocardial infarction (inflammation caused by injury). One would have a reasonable expectation of success because Dolmatova demonstrated that ischemia results in an increase in Panx1 activity in cardiomyocytes, which leads to increased ATP secretion that contributes to fibrosis.
Regarding claim 14, as stated above, EP ‘930 teaches SEQ ID NO: 1 (Sequence Listing).
Regarding claim 15, as stated above, EP ‘930 teaches that a “variant” of the peptide shall be taken to mean a peptide having an amino acid sequence that is substantially identical to SEQUENCE ID NO. 1, but which is altered in respect of one or more amino acid residues, most preferably 3 amino acids ([0067]).
Regarding claim 18, EP ‘930 teaches that peptide structure modifications can include the generation of retro-inverso peptides comprising the reversed sequence encoded by D-amino acids ([0066], [0132], [0160]).
Regarding claim 21, EP ‘930 teaches that therapeutically effective variants of the peptide SEQUENCE ID NO. 1 include the peptides SEQ ID NO: 2-65 and 68-73, which are identical to the instant SEQ ID NO: 2-65 and 68-73 ([0097]-[0102]); Sequence Listing starting on Pg 33). SEQUENCE ID NO. 1 of EP ‘930 also reads on the instant SEQ ID NO: 90.
Regarding claims 23-25, EP ‘930 teaches that the peptides taught can be chemically modified to increase their stability. The modifications can include, but are not limited to, modifications to side chains, incorporation of unnatural amino acids and/or their derivatives during peptide synthesis and the use of cross-linkers and other methods that impose conformational constraint on the peptides or their analogs ([0066], with detailed examples provided starting on line 24). Other types of modifications taught by EP ‘930 include conjugating the peptide with a binding partner, cyclisation, addition of N- or C-terminal, or side chain, protecting groups, replacing L-amino acids with D-isomers, amino acid modification, increased plasma protein binding, increased albumin binding ([0132]-[0156], [0163], [0165], [0167]-[0184]).
Regarding claim 32, as stated above, EP ‘930 teaches a peptide having up to 50 amino acids in length and comprising SEQ ID NO: 1 ([0018, 0019, 0066]; Sequence Listing).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 14, 15, 21, 23-25 and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 and 11-12 of U.S. Patent No. 10,729,636 B2 (US ‘636). Although the claims at issue are not identical, they are not patentably distinct from each other because practicing the instant method claims reads on the claims of US ‘636.
Claim 1 of US ‘636 recites a composition comprising a peptide of up to 50 amino acids, the peptide comprising the amino acid sequence of SEQ ID NO: 1, or a variant thereof, the variant comprising no more than 3 amino acid alterations relative to SEQ ID NO: 1. SEQ ID NO: 1 of US ‘636 and the instant SEQ ID NO: 1 are identical.
Dependent claims include species of SEQ ID NO: 1 (claims 2 and 6), modifications to SEQ ID NO: 1 (claims 3, 4, 11, and 12), and a pharmaceutical composition thereof for use a method of treating diabetes or pre-diabetes (claim 5).
Claims 1, 14, 15, 18, 19, 21, 22, 25, and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5-10 and 15 of U.S. Patent No. 12,398,180 B2 (US ‘180) as evidenced by Heyens et al. (Liver Fibrosis in Non-alcoholic Fatty Liver Disease: From Liver Biopsy to Non-invasive Biomarkers in Diagnosis and Treatment. Front Med (Lausanne). 2021 Apr 14;8:615978.). Although the claims at issue are not identical, they are not patentably distinct from each other because practicing the instant method claims reads on the claims of US ‘180.
Claim 1 of US ‘180 recites a method for the treatment of non-alcoholic fatty liver disease (NAFLD) in a mammal having NAFLD, the method comprising: administering: (a) a peptide having up to 50 amino acids and comprising SEQ ID NO: 1, or (b) a therapeutically effective variant of SEQ ID NO: 1 comprising 1 to 5 alterations compared with SEQ ID NO: 1, in which each alteration is independently selected from insertion of an amino acid, addition of an amino acid, deletion of an amino acid, and conservative substitution of an amino acid, to the mammal.
SEQ ID NO: 1 of US ‘180 and the instant SEQ ID NO: 1 are identical. The instant specification teaches the instant SEQ ID NO: 1 can be used to treat liver diseases such as NAFLD (Pg 9, lines 14-20). Further, as evidenced by Heyens, the manifestation of NAFLD is associated with damage (injury) and inflammation to the liver and fibrosis (Abstract; Pg 2, “Pathophysiology of NAFLD/NASH”).
Dependent claims include the species of NAFLD (claim 2), the species of SEQ ID NO: 1 (claim 3), D-amino acid substitutions (claims 5-8) and modifications to the peptides (claims 9 and 10). SEQ ID NO: 2 and 3 of US ‘180 are identical to the instant SEQ ID NO: 86 and 87, respectively.
Conclusion
No claim is allowed.
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/SARA E KONOPELSKI SNAVELY/Examiner, Art Unit 1658
/Melissa L Fisher/Supervisory Patent Examiner, Art Unit 1658
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