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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/23/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The listing of references in the specification (starting on page 104) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because of the following informalities:
The acronym “DSS” which appears for the first time in the “description of the figures” section in page 7, line 2, is not defined in the specification until page 101, line 12. The acronym should be defined in the specification the first time it is used, for clarity. The same is the case with “DON”, which is not defined in the description of the drawings at all, and it is not defined in the spec. until page 102, line 11.
A Detailed Description of the Drawings section also appears to be missing from the disclosure.
Appropriate correction is required.
Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show which “INF” compound is being depicted, as described in the specification. Particularly, Figures 2-3 only show “INF” while descriptions in the spec. say “INF176”.
Figures 4-5 fail to show what DON is. The description of the drawings (page 7) doesn’t have this information either.
Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Status of the Claims
Claims 1-17 are pending in this application.
Claim Objections
Claims 1, 3, 6, 10, 12-13, and 15-17 are objected to because of the following informalities:
In claim 1:
missing “in” after “individual” in line 2, to read: “individual in need…”
the statements “R8 is as defined above;” and “R9 is as defined above;” are redundant and should be removed (third and fifth lines from bottom of page 6 in claims).
Claim is missing a period at the end, after “individual”.
Add preposition “A” before “Method of preventing…” at the beginning of the claim.
The p in –(R7-R8)p should be a subscript in the text of the claim (i.e. –(R7-R8)p), as it appears in Formula I.
In claims 1 and 10, the limitation: “bonded to the stereogenic carbon in alpha of a preferably natural…” should read: “bonded to the stereogenic carbon alpha to the carboxyl group of a natural, optionally protected, amino acid selected from…” or something to that effect.
In claims 3, 6, 12-13, and 15, the structures provided are blurry and difficult to read in some cases.
In claim 10:
the statements: “R8 is as defined above;” “R9 is as defined above;” “R1 and R2 are as defined above,” are redundant and should be removed.
The limitation below, should read: “wherein at least one of R1 or R2 are in the 2 position of A when A is phenyl” or something to that effect.
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Furthermore, the limitation above appears to be considerably repeated in the claim when Applicant states the limitation shown below, which also states that when A is phenyl, at least one of R1-2 cannot be H and has to be in the 2 position of phenyl A. Although the limitation below also requires R6 and R7 to not form a ring, Applicant does not specify whether both limitations are required or if one or the other is required – see 112(b).
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In claims 16 and 17, add preposition “A” before “Medicament…” and “Pharmaceutical…”, respectively, to read: “A medicament…” and “A pharmaceutical…”, respectively.
Appropriate correction is required.
Claim Interpretation
Claim 10 states X is selected from N, O, S…, or can be O, S… when Y is O (see 112(b) for “can be” language) – the broadest reasonable interpretation of the claim has been applied to encompass embodiments in which X “can be” O or S or N when Y is O.
The term “cycloalkyl” is defined in the specification as encompassing saturated and partly saturated hydrocarbon rings (page 14, last para.).
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 1-9 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 the treatment of diseases mediated by NLRP3 inflammasome, does not reasonably provide enablement for prevention of the same. 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 use of the invention commensurate in scope with these claims.
The applicant’s attention is drawn to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1998), where the court set forth eight factors to considers 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 examples; and (8) the quantity of experimentation necessary.
Breadth of Claims
Claims 1 and 8 broadly encompasses a method of treating and/or preventing any condition or disorder mediated by the NLRP3 inflammasome (any inflammatory, autoimmune, cardiovascular, metabolic, and neoplastic disease and/or disorder, etc.), in any individual in need thereof, comprising administration of any of the compounds of Formula I, or pharmaceutically acceptable derivatives thereof. Claim 9 slightly narrows the scope of claim 1 by referring to the treatment or prevention of cryopyrin-associated periodic syndromes (CAPS), asthma, arthritis, inflammation induced by viral infections, Alzheimer’s disease (AD), cardiovascular diseases, non-alcoholic steatohepatitis (NASH), obesity, type 1 diabetes, and cancers, like stomach, lung, head/neck cancers, and melanoma.
The term “individual in need” was not defined in the specification. Accordingly, the broadest reasonable interpretation of the term is taken to be any animal (humans, other primates, dogs, cats, squid, etc.).
The term “prevention” is not defined in the specification. The Oxford English Dictionary (2024) defines “prevent” as to “preclude the occurrence” and thus claim 1 encompasses embodiments in which the claimed compounds can preclude the many diseases mediated by NLRP3 inflammasome. See definition II.9.a. Obtained from oed.com [retrieved on 2025-03-05] URL:httos://www.oed.convdictionary/prevent_y?t=true).
Nature of the invention/ State of the Prior Art/ Predictability in the Art
The CDC reports that currently, type 1 diabetes cannot be prevented, however, it can be treated effectively. Obtained from cdc.gov [retrieved on 02/02/2026] <URL: https://www.cdc.gov/diabetes/about/about-type-1-diabetes.html>) Pub. Date: May 15, 2024.
The NHS reports that there is no certain way to prevent Alzheimer’s disease. Obtained from nhs.uk [retrieved on 02/02/2026] <URL: https://www.nhs.uk/conditions/alzheimers-disease/prevention/>) Pub. Date: July 04 2024.
The American Cancer Society reports there is no sure way to prevent stomach cancer (gastric cancer), and there are only things we can do to lowers risks. Obtained from cancer.org [retrieved on 02/02/2026] <URL: https://www.cancer.org/cancer/types/stomach-cancer/causes-risks-prevention/prevention.html>) Pub. Date: April 30, 2025.
Finally, the medical arts are also generally considered to be unpredictable making the goal of achieving prevention in this case even less likely. See Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). See also In re Fisher, 427, F. 2d 833, 166, USPQ 18 (CCPA 1970) (“In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involve.”).
Level of One of Ordinary Skill
The level of one of ordinary skill in the art would be high, likely an M.D. or Ph.D. in the medical arts (e.g., studying treatment of cancers, neurological, and metabolic conditions). See Orthopedic Equip. Co. v. All Orthopedic Appliances, Inc., 707 F.2d 1376 at 1381–82 (Fed. Cir. 1983) (Factors that may be considered in determining level of ordinary skill in the art include: … type of problems encountered in the art …”).
Guidance/Working Examples
In page 100, applicant discloses cytotoxicity studies of THP-1 cells (monocytic leukemia cell line) with “test compounds” at different concentrations – unclear which compounds were actually tested, though from page 98, last para. line 24, it appears that only compounds INF176 and 177 (shown below) were tested.
In page 101, Applicant shows compound INF176 is able to inhibit NLRP3-dependent cell pyroptosis induced by LPS/ATP in a dose dependent manner; and that compound INF176 inhibits IL-1β release from human macrophages (Figures 1A and B).
Applicant states in vivo experiments with INF176 in mice improved the systemic tissue parameters associated with colitis in DSS induced colitis (Example 50 of spec. and Figures 2-3). Applicant notes that INF176 improves slowing of colon transit, and that in vitro studies demonstrate improvement in colon contractions.
In page 102, Applicant discloses in vivo mice models with INF176, starting chronic administration in the earliest stages of the disease, before the appearance of the first symptoms, and notes a counteraction in cognitive decline and reduced expression of p-tau protein with results comparable to donepezil, a medicament approved for treatment (not prevention) of AD (Figures 4A-C).
Lastly, Applicant discloses molecular docking studies of INF177 – a metabolite of INF176 – in Table 3 (page 103).
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Therefore, the specification provides no working examples for the prevention of type 1 diabetes, Alzheimer’s, or any cancers. Particularly, the specification does not enable one of ordinary skill to treat or prevent the many diseases claimed with all of the many compounds encompassed by instant Formula I, since the activity of only INF176 and 177 was actually tested.
Degree of Experimentation
To practice the invention as claimed, the skilled artisan would have to screen each of the many compounds encompassed by the broad genus in instant Formula I in order to determine whether the compounds meet the functional limitations of the claim for the treatment and/or prevention of any of the many diseases encompassed by the claims (cryopyrin-associated periodic syndromes (CAPS), asthma, arthritis, inflammation induced by viral infections, Alzheimer’s disease (AD), cardiovascular diseases, non-alcoholic steatohepatitis (NASH), obesity, type 1 diabetes, and cancers, like stomach, lung, head/neck cancers, and melanoma). In addition, the skilled artisan would need to determine which subjects would benefit from treatment and prevention of these diseases (humans, other primates, cats, dogs, squid, etc.) by administering the instantly claimed compounds to a statistically significant pool of subjects from each species. Prevention the many aforementioned conditions would require long-term monitoring of each patient for appearance of any new cryopyrin-associated periodic syndromes (CAPS), asthma, arthritis, inflammation induced by viral infections, Alzheimer’s disease (AD), cardiovascular diseases, non-alcoholic steatohepatitis (NASH), obesity, type 1 diabetes, and cancers, like stomach, lung, head/neck cancers, and melanoma, etc. Thus, the quantity of experimentation in this area would be extremely large, since there are a significant number of parameters that would have to be studied beyond the preliminary studies provided. Furthermore, the ultimate outcome of such experimentation is completely unpredictable.
In sum, taking into consideration the Wands factors outlined above, an undue amount of experimentation would be required here to make and use the full scope of the claimed invention.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
In claims 1-2 and 10, the terms “preferably”, “more preferably”, and “most preferably” (every occurrence) are relative terms which render the claims indefinite. The terms are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Regarding claims 1 and 10, the phrase "for example" renders the claims indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Further regarding claims 1 and 10, the term “can be” or “can occupy” (every occurrence) also render the claims indefinite because they raise a question as to whether the limitations following the terms are or aren’t required. Examiner suggests replacing these terms with “is” or “are” as appropriate.
Further regarding claim 1, the claim reads: “Method of … with compounds of general Formula (I) … and their enantiomers, diastereomers, rotamers, or mixtures thereof; and the pharmaceutically acceptable salts or solvates thereof, said method comprising administering a therapeutically effective amount of said compound to said individual”. As written, it is unclear if the “said compound” refers only to the “compounds of Formula I” or to the “compounds of Formula I, enantiomers, diastereomers, rotamers, or mixtures thereof; and the pharmaceutically acceptable salts or solvates thereof.”
Claims 1-9 are rejected for depending upon the limitations of claim 1.
Claims 11-17 are rejected for depending upon the limitations of claim 10.
Regarding claims 9 and 10, the phrase "such as" renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 9 recites the broad recitations: “viral infections”, “ALS correlated symptoms”, “cardiovascular diseases”; and the claim also recites “(such as those caused by the SARS-CoV-2 (COVID-19) virus)”, “(such as gastrointestinal disorders)”, “such as hypertension…)” which are the narrower statements of the range/limitations. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Examiner suggests removing the parentheses and information therein.
Further regarding claim 9, the limitation “tumors comprising stomach cancer, head/neck cancers, lung cancer, melanoma, and myelodysplastic syndromes” is indefinite because it is unclear if Applicant intends a single tumor comprising all of “stomach cancer, head/neck cancers, lung cancer, melanoma, and myelodysplastic syndromes” or if Applicant intends “a tumor selected from the group consisting of stomach cancer, head/neck cancers, lung cancer, melanoma, and myelodysplastic syndromes”. On a related note, the claim is indefinite for being an improper Markush – does applicant intend “tumors selected from the group consisting of …”?
Claim 10 is further unclear because it lists conditions without providing a resolution as to how the conditions are further limiting. For example, the claim reads: “wherein in compounds of Formula I, when R6 and R7 do not form a ring: - when A is …” (starting on 9th line from bottom of page 22 of claims to end of claim 10). Applicant lists several conditional statements beginning with “When…” however, provides no resolution at the end of the claim.
Does Applicant intent to say that “when in the compounds of Formula I R6 and R7 do not form a ring, then A is phenyl…” ? This is unclear. Therefore, for the purposes of applying art, these conditionals will be interpreted as other “preferred” embodiments, and not as further limiting in the scope of the claims.
Also in claim 10, the limitation below needs clarification:
Applicant states:
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Here, does applicant intend to say that, “when A is phenyl, then at least one of R1 and R2 is in the 2-position and is not H and R6 and R7 do not form a ring”? or does applicant intend to say that “when A is phenyl and R6 and R7 do not form a ring, then at least one of R1 and R2 is not H and is at the 2 position of phenyl ring corresponding to A”?
In claim 10, Applicant also states:
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These limitations state almost the same thing; however, the first limitation above requires R6 and R7 to not form a ring. Applicant does not specify whether both of these limitations are required, or if one or the other is required. Therefore, it is unclear when the two positions of the phenyl corresponding to A has to be substituted . . . is it only when R6 and R7 to not form a ring or not? – For the purposes of applying art, these limitations will be interpreted as: “when A is phenyl and R6 and R7 do not form a ring, then at least one of R1 and R2 is not H and is at the 2 position of phenyl ring corresponding to A.”
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.
Claim 12-13 and 15 is 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 12-13 and 15 are rejected for failing to further limit claim 10, from which they depend. Claim 10 has the limitation below (see 112(b)), which has been interpreted to mean that “when A is phenyl and R6 and R7 do not form a ring, then at least one of R1 and R2 is not H and is at the 2 position of phenyl ring corresponding to A”.
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However, claims 12-13 and 15 show the compounds below, wherein A is phenyl, R6 and R7 do not (necessarily) form a ring, and neither of R1-2 are limited to the 2-position of phenyl:
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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 § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3-4, and 7-9 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Neamati et al. (WO 2007/081966 A2) (“Neamati”).
Regarding claims 1, 3-4, and 7-9, Neamati discloses their compound CT23 below (page 37, Table 4), which anticipates the instant structures when A is phenyl; R1 and R2 are H; the dashed line forms a double bond; X is SO2; Y is O; R3 is H; R6 is Me; and R4 is substituted aryl. Neamati discloses their compound as showing anticancer activity against colon and breast cancer cell lines. Neamati claims a method of treating diseases like lung cancer, diabetes, immune and non-immune inflammatory diseases, etc., comprising administration of their compounds (see Neamati’s claims 1, 18, 23-25).
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Further regarding claims 1 and 7, Applicant is advised that a recitation of the intended use of the claimed invention, such as the limitation: “wherein the compound is an NLRP3 inflammasome medicament” or “disorders mediated by the NLRP3 inflammasome” in the instant application, must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Note: MPEP 2111.02. In the instant case, Neamati discloses their compound for the same conditions claimed, therefore, the recitations: “wherein the compound is an NLRP3 inflammasome medicament” and “disorders mediated by the NLRP3 inflammasome” are not further limiting.
Applicant is further advised that products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
Claims 10-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Spyrakis et al. (Eur. J. Med. Chem., 42, 2007, 921-933) (“Spyrakis”).
Regarding claims 10-13, Spyrakis discloses the compound 7 below (scheme 1), which anticipates the instant compounds when A is substituted phenyl, with R1-2 being substituted alkyl; R3 is H; X is SO2; R4 is substituted phenyl; Y is N; and R6-7 join to form a heterocycle (therefore the 2-position does not require substitution – see 112(b)); and R8 is H.
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Claims 10 and 12-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Das et al. (Chem. Pharm. Bull., 2007, 55(8) 1274—1276) (“Das”).
Regarding claims 10 and 12-13, Das teaches the compound 1 below (Table 1, col. 2, page 1274), which anticipates the instant compounds when X is S; R4 is phenyl; A is phenyl; and one of R1-2 is Cl at the 2-position of phenyl (since R6-7 do not form a ring); Y is O; and R6 is Me.
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(1)
Claims 10 and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by CAS 2386635-28-3; CAS Registry File Accessed 02/03/2026 from STN; entered into STN Dec. 2nd, 2019).
This compound anticipates claims 10 and 12 when A is phenyl; R1-2 are F (one at the 2-position since R6-7 do not form a ring); Y is O; R6 is H; X is S; R3 is H; and R4 is methyl (C1 alkyl).
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Claims 10-12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by CAS 1348574-49-1; CAS Registry File Accessed 02/03/2026 from STN; entered into STN Dec. 4th, 2011).
This compound anticipates claims 10-12 when A is phenyl; R1-2 are H (since R6-7 do not form a ring, both R1-2 can be H – see 112(b)); Y is N; R6 and R7 joined to make a heterocycle; wherein m is 0 and n is 2; R8 is -CO2(alkyl); X is S; R3 is H; and R4 is partially unsaturated and substituted alkyl.
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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.
Claims 10, 12-13, and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Neamati et al. (WO 2007/081966 A2) (“Neamati”); as applied to claims 1, 3-4, and 7-9; in view of Meanwell et al. (J. Med. Chem. 2011, 54, 2529–2591) (“Meanwell”).
The teachings of Neamati are disclosed above and incorporated herein.
Neamati further discloses their compounds of Formula V below [0006] as well as their preferred embodiment CT23 (page 32), wherein each of R1-3 can be H, halogen, alkyl, substituted or unsubstituted aryl/ heteroaryl; wherein substituents can be halogen etc.
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Instant claim 10 has the proviso that when A is phenyl and R6-7 do not form a ring, then one of R1 or R2 cannot be H and the 2-position of A has to be substituted. While Neamati’s preferred embodiment CT23 does not have a halogen substituent at the 2-position of the phenyl corresponding to instant ring A, Neamati teaches their R2 can be aryl substituted with halogen. One of ordinary skill would have had a reasonable expectation of success in arriving at the instant structure, since the phenyl A only has five possible positions for substitution and a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2143(E) KSR, 550 U.S. at 421, 82 USPQ2d at 1397. Therefore, Neamati discloses a subgenus of the broad genus claimed in the instant application.
Furthermore, the teachings of Meanwell are relied upon as outlined below:
Meanwell teaches that the design of bioisosteres frequently introduces structural changes that can be beneficial depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry. In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates (abstract). Meanwell specifically teaches H and F as classical, monovalent bioisosteres (table 1, col. 1, page 2529; and page 2531, col. 1, last para.) – “The unique properties of fluorine have led to its widespread application in drug design as an isostere for hydrogen, since incorporation of this halogen can productively modulate a range of properties of interest to medicinal chemists”.
Therefore, regarding claims 10 and 12-13, one having ordinary skill in the art would have found the claimed compounds prima facie obvious, since they are generically embraced by Neamarti’s disclosed formula in view of Meanwell; In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). See MPEP 2144.08. The requisite motivation for arriving at the claimed compounds stems from the fact that they fall within the generic class of tubulin inhibitors disclosed by Neamarti as being useful for the treatment of cancers, neurodegenerative, and inflammatory conditions; further in view of Meanwell’s disclosure that the design of bioisosteres frequently introduces structural changes that can be beneficial, and their teaching that H and F are known bioisosteres in medicinal chemistry. Accordingly, one having ordinary skill in the art would have been motivated to and had a reasonable expectation of success in preparing Neamari’s compounds with a fluorine on the phenyl corresponding to instant ring A.
Furthermore, Applicant is advised that H vs. Me is considered an obvious modification in the absence of superior, unexpected results. Note In re Wood 199 USPQ 137; In re Lohr 187 USPQ 548 and In re Bowers 149 USPQ 573. Note also In re Fauque 121 USPQ 425 in which differences were 2H’s vs 2 methyl groups. Also see MPEP 2144.09. Therefore, Neamarti’s compound reads on the instant compounds when one of R1-2 is C1 alkyl.
Regarding claims 16-17, Neamarti claims a pharmaceutical composition comprising their compounds of and an acceptable carrier (reading on excipient) (Neamarti’s claim 11).
Claims 1-4 and 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Spyrakis et al. (Eur. J. Med. Chem., 42, 2007, 921-933) (“Spyrakis”); as applied to claims 10-13; in view of Mihara et al. (Endocrinology, 2010, 151(2):513–519) (“Mihara”).
The teachings of Spyrakis are disclosed in the 102-section above and incorporated herein.
Regarding claims 1-4 and 7-9, Spyrakis discloses the compound 7 above (scheme 1), which anticipates the instant compounds when A is substituted phenyl, with R1-2 being substituted alkyl; R3 is H; X is SO2; R4 is substituted phenyl; Y is N; and R6-7 join to form a heterocycle, wherein R8 is H. Spyrakis discloses their compound as a thrombin inhibitor (see 1ett entry, table 1, page 923).
While Spyrakis does not specifically teach their compound for the treatment of inflammatory diseases associated with NLRP3 inflammasome; the teachings of Mihara are relied upon for these disclosures.
Mihara teaches that the binding of thrombin to its receptor stimulates inflammatory cytokines including IL-6 and MCP-1, leading to the development of insulin resistance and type 2 diabetes (abstract). Thus, Mihara suggests that thrombin inhibition ameliorates insulin resistance in obese, diabetic mice (abstract).
Therefore, regarding instant claims 1-4 and 7-9, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to administer Spyrakis’ compound 7 for the treatment of inflammatory diseases such as type 2 diabetes in view of Mihara. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Spyrakis teaches their compound as a thrombin inhibitor (ΔG of -8 kcal/mol for binding – indicating a favorable, exergonic process); further because Mihara teaches thrombin inhibition ameliorates insulin resistance in obese, diabetic mice by blocking stimulation of inflammatory cytokines.
Applicant is advised that similar properties may normally be presumed when compounds are very close in structure. Dillon, 919 F.2d at 693, 696, 16 USPQ2d at 1901, 1904. See also In re Grabiak, 769 F.2d 729, 731, 226 USPQ 870, 871 (Fed. Cir. 1985) (“When chemical compounds have very close structural similarities and similar utilities, without more a prima facie case may be made.”). Thus, evidence of similar properties or evidence of any useful properties disclosed in the prior art that would be expected to be shared by the claimed invention weighs in favor of a conclusion that the claimed invention would have been obvious. Dillon, 919 F.2d at 697-98, 16 USPQ2d at 1905; In re Wilder, 563 F.2d 457, 461, 195 USPQ 426, 430 (CCPA 1977); In re Linter, 458 F.2d 1013, 1016, 173 USPQ 560, 562 (CCPA 1972) (see MPEP 2144.08(d)).
Further regarding claims 1 and 7, Applicant is advised that a recitation of the intended use of the claimed invention, such as the limitation: “wherein the compound is an NLRP3 inflammasome medicament” or “disorders mediated by the NLRP3 inflammasome” in the instant application, must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Applicant is further reminded that products of identical chemical composition cannot have mutually exclusive properties." A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
Claims 1, 3-4, 7-10, 12-13, and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Pierau et al. (US 2006/0046978 A1) (“Pierau”); in view of Meanwell et al. (J. Med. Chem. 2011, 54, 2529–2591) (“Meanwell”).
Regarding claims 1, 3-4, 7-10, 12-13, and 16-17, Pierau discloses their compounds of general formula I below [0030], wherein R can by heteroalkyl, alkyl, etc. Pierau specifically discloses their compound 1 below [0044], which reads on the instant compounds when A is phenyl; X is S; Y is N; p = 1; R6 is H; and R7 is a branched, substituted C3 alkyl group. Pierau teaches their compounds as DPP4 inhibitors for the treatment of diseases like type 2 diabetes and metabolic conditions [0040]-[0041] – which reads on the intended use of the instant application. Further regarding claims 7 and 16-17, Pierau claims a pharmaceutical composition comprising their compounds and an acceptable carrier (reading on excipient) (Pierau’s claim 3) – reading on a medicament.
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While Pierau does not teach their compounds wherein the group corresponding to instant R4 is not H, as required by the instant claims 1 and 10, Applicant is reminded that H vs. Me is considered an obvious modification in the absence of superior, unexpected results. Therefore, Pierau’s compounds read on the instant compounds when R4 is C1 alkyl.
While instant claim 10 has the proviso that when A is phenyl then one of R1 or R2 cannot be H; the teachings of Meanwell are relied upon for these disclosures.
Meanwell teaches that the design of bioisosteres frequently introduces structural changes that can be beneficial depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry. In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates (abstract). Meanwell specifically teaches H and F as classical, monovalent bioisosteres (table 1, col. 1, page 2529; and page 2531, col. 1, last para.) – “The unique properties of fluorine have led to its widespread application in drug design as an isostere for hydrogen, since incorporation of this halogen can productively modulate a range of properties of interest to medicinal chemists”.
Therefore, regarding claims 1, 3-4, 10, and 12-13, one having ordinary skill in the art would have found the claimed compounds prima facie obvious, since they are generically embraced by Pierau’s disclosed formula in view of Meanwell. The requisite motivation for arriving at the claimed compounds stems from the fact that they fall within the generic class of DPP4 inhibitors disclosed by Pierau as being useful for the treatment of metabolic and inflammatory conditions (see Pierau’s claim 8); in view of Meanwell’s disclosure that the design of bioisosteres frequently introduces structural changes that can be beneficial, and their teaching that H and F are known bioisosteres in medicinal chemistry. Accordingly, one having ordinary skill in the art would have been motivated to and had a reasonable expectation of success in preparing any of the compounds embraced by the disclosed generic formula, including those encompassed by the claims.
Further regarding claims 1, 3-4, and 7-9, Pierau teaches their compounds as DPP4 inhibitors for the treatment of diseases like type 2 diabetes and metabolic conditions [0040]-[0041], as well as neurodegenerative and metastatic disorders (see Pierau’s claim 8).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to administer Pierau’s in view of Meanwell’s compounds for the treatment of type 2 diabetes, neurodegenerative disorders, etc. as claimed in the instant application. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Pierau teaches their compounds as DPP4 inhibitors, and discloses pharmaceutical compositions thereof, as useful for the treatment of metabolic disorders.
Applicant is reminded that similar properties may normally be presumed when compounds are very close in structure. Dillon, 919 F.2d at 693, 696, 16 USPQ2d at 1901, 1904. See also In re Grabiak, 769 F.2d 729, 731, 226 USPQ 870, 871 (Fed. Cir. 1985) (“When chemical compounds have very close structural similarities and similar utilities, without more a prima facie case may be made.”). Thus, evidence of similar properties or evidence of any useful properties disclosed in the prior art that would be expected to be shared by the claimed invention weighs in favor of a conclusion that the claimed invention would have been obvious.
Further regarding claims 1 and 7, Applicant is advised that a recitation of the intended use of the claimed invention, such as the limitation: “wherein the compound is an NLRP3 inflammasome medicament” or “disorders mediated by the NLRP3 inflammasome” in the instant application, must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Applicant is further reminded that products of identical chemical composition cannot have mutually exclusive properties." A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
Claims 14 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Das et al. (Chem. Pharm. Bull., 2007, 55(8) 1274—1276) (“Das”); as applied to claims 10 and 12-13.
The teachings of Das are disclosed in the 102-section above and incorporated herein.
Das teaches the compounds 1 and 2 below (Table 1, col. 2, page 1274), which render the instant compounds INF42 and Br7 obvious.
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Regarding claim 14, Das’ compound 1 differs from instant INF42 only in that instant R6 is ethyl, versus methyl. Applicant is advised that compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Regarding claim 15, Das’ compound 2 differs from instant Br7 only in the addition of a methyl ester vs a carboxylic acid and the position of methoxy on the phenyl ring corresponding to A. Applicant is reminded that H vs. Me is considered an obvious modification in the absence of superior, unexpected results. Furthermore, Applicant is advised that a novel useful compound that is isomeric with the prior art compound is unpatentable unless it possesses some unobvious or unexpected beneficial property not possessed by the prior art compound. In re Norris, 179 F.2d. 970, 84 USPQ 458 (CCPA 1970). Therefore, it would have been obvious to one of ordinary skill to expect similar properties of structurally similar compounds since they are suggestive of one another. It has been held that a compound, which is structurally isomeric with a compound of the prior art, is prima facie obvious absent unexpected results. In re Finely, 81 USPQ 383 (CCPA 1949); 84 USPQ 458 (CCPA 1950).
Therefore, regarding claims 14-15, one having ordinary skill in the art would have found the claimed compounds prima facie obvious, since they are generically embraced Das’ disclosure and methods of making related compounds. The requisite motivation for arriving at the claimed compounds stems from the fact that they fall within the generic class of compounds disclosed by Das. Accordingly, one having ordinary skill in the art would have been motivated to prepare any of the compounds embraced by the disclosed generic formula, including those encompassed by the claims.
Claims 1 and 3-9 are rejected under 35 U.S.C. 103 as being unpatentable over Das et al. (Chem. Pharm. Bull., 2007, 55(8) 1274—1276) (“Das”); as applied to claims 10 and 12-15; further in view of Neamati et al. (WO 2007/081966 A2) (“Neamati”); and Meanwell et al. Meanwell et al. (J. Med. Chem. 2011, 54, 2529–2591) (“Meanwell”).
Regarding claims 1 and 3-6, Das teaches the compounds 1 and 2 below (Table 1, col. 2, page 1274), which render the instant compounds INF42 and Br7 obvious.
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Regarding claim 5, Das’ compound 1 differs from instant INF42 only in that instant R6 is ethyl, versus methyl. Applicant is reminded that compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties.
Regarding claim 6, Das’ compound 2 differs from instant Br7 only in the addition of a methyl ester vs a carboxylic acid and the position of methoxy on the phenyl ring corresponding to A. Applicant is reminded that H vs. Me is considered an obvious modification in the absence of superior, unexpected results. Furthermore, Applicant is reminded that a novel useful compound that is isomeric with the prior art compound is unpatentable unless it possesses some unobvious or unexpected beneficial property not possessed by the prior art compound. Therefore, it would have been obvious to one of ordinary skill to expect similar properties of structurally similar compounds since they are suggestive of one another. It has been held that a compound, which is structurally isomeric with a compound of the prior art, is prima facie obvious absent unexpected results.
Therefore, regarding claims 1 and 3-6, one having ordinary skill in the art would have found the claimed compounds prima facie obvious, since they are generically embraced Das’ disclosure and methods of making related compounds. The requisite motivation for arriving at the claimed compounds stems from the fact that they fall within the generic class of compounds disclosed by Das. Accordingly, one having ordinary skill in the art would have been motivated to prepare any of the compounds embraced by the disclosed generic formula, including those encompassed by the claims.
While Das does not teach their compounds for the treatment of inflammatory conditions; the teachings of Neamati and Meanwell are relied upon for these disclosures.
Neamati discloses their compound CT23 below (page 37, Table 4), which anticipates the instant structures when A is phenyl; R1 and R2 are H; the dashed line forms a double bond; X is SO2; Y is O; R3 is H; R6 is Me; and R4 is substituted aryl. Neamati discloses their compound as showing anticancer activity against colon and breast cancer cell lines. Neamati claims a method of treating diseases like lung cancer, diabetes, immune and non-immune inflammatory diseases, etc., comprising administration of their compounds (claims 1, 18, 23-25).
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Meanwell teaches that the design of bioisosteres frequently introduces structural changes that can be beneficial depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry. In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates (abstract). Meanwell teaches -S- and -SO2- as common divalent isosteres in medicinal chemistry, and shows that their replacement in a lead compound is an obvious and routine modification in lead compounds and drugs (Table 10 and para. immediately after, page 2536).
Therefore, regarding claims 1 and 3-9, it would have been prima facie obvious to one of ordinary skill prior to the effective filing of the claimed invention to administer Das’ compounds for the treatment of inflammatory diseases (such as lung cancer, diabetes, immune and non-immune inflammatory diseases, etc.) in view of Neamati and Meanwell. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Das discloses their compounds (with S in the position corresponding to instant X); Neamati discloses their compound CT23 (with SO2 in the position corresponding to instant X) and teaches that they are effective for the treatment of inflammatory conditions; further because Meanwell teaches that bioisosteric modifications may be beneficial to improve lead and drug compound potency, and other properties, and their teaching that -S- and -SO2- are common divalent isosteres and that their replacement is routine in medicinal chemistry for lead compound optimization.
Applicant is reminded that similar properties may normally be presumed when compounds are very close in structure. (“When chemical compounds have very close structural similarities and similar utilities, without more a prima facie case may be made.”). Thus, evidence of similar properties or evidence of any useful properties disclosed in the prior art that would be expected to be shared by the claimed invention weighs in favor of a conclusion that the claimed invention would have been obvious.
Further regarding claims 1 and 7, Applicant is reminded that a recitation of the intended use of the claimed invention, such as the limitation: “wherein the compound is an NLRP3 inflammasome medicament” or “disorders mediated by the NLRP3 inflammasome” in the instant application, must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. In the instant case, Neamati discloses their compound for the same conditions claimed, therefore, the recitations: “wherein the compound is an NLRP3 inflammasome medicament” and “disorders mediated by the NLRP3 inflammasome” are not further limiting.
Applicant is further reminded that products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
Conclusion
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627