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 .
Election/Restrictions
Applicant’s response to the restriction/ election requirement with traverse from 5/26/2026 is acknowledged. Applicant has made the following election.
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It is noted that the election of “disease species” is non-responsive, because “inflammasome-related diseases” is a genus, not a species. Moreover, the specification does not even define this claim term. To the extent that there is a reference to it, the specification simply lumps together the large group of diseases of claim 63- inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases- into a single long sentence of no definition whatsoever of which is which, and with further large genuses of diseases of vastly different etiology and pathology. Specifically, paragraph [0216] of the specification provides: “The inflammasome-related disease, the immune disease, the inflammatory disease, the autoimmune disease and/or the autoinflammatory disease may be specifically selected from the group consisting of: autoinflammatory fever syndromes (such as cryo-pyrin-associated periodic syndromes), sickle-cell anemia, systemic lupus erythematosus, liver-related diseases (such as chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis, alcoholic steatohepatitis and alcoholic liver disease), inflammatory arthritis-related diseases (such as gout, chondrocalcinosis, osteoarthritis, rheumatoid arthritis and acute or chronic arthritis), kidney-related diseases (such as hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis-associated inflammation, type I or type II diabetes and complications thereof (such as nephropathy and retinopathy)), neuroinflammation-related diseases (such as brain infection, acute injury, multiple sclerosis, Alzheimer's disease and neurodegenerative diseases), cardiovascular and metabolic disorders or diseases (such as cardiovascular risk reduction (CvRR), atherosclerosis, type I and type II diabetes and related complications, peripheral artery disease (PAD), acute heart failure and hypertension), wound healing, scar formation, inflammatory skin diseases (e.g., acne and hidradenitis suppurativa), asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases/conditions (e.g., myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis, lung cancer and colon cancer).”
Further, Applicant did not even make any articulated traverse concerning the election of a single species of a disease. There is some very vague wording, which in no way explains any ground for traverse. Also, how can a compound and a disease share a single general inventive concept?
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In view of the above, although the Examiner did not issue miscellaneous communication for the non-responsive election, a rejection over this claim term has further been made below under 35 USC 112(b).
Further, the Examiner disagrees with Applicant’s traverse regarding “a core pyridazine-containing structure”. A pyridazine is this:
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Applicant’s claimed core structure is not even a pyridazine ring, but is built around this structure:
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But this still even is not a single core structure, because recited within the definitions of substituents within it are multiple diverse core structures. As a single non-limiting example, R2 and R3, together with the atoms to which they are attached, for a 5-6 membered cyclic hydrocarbon, phenyl, a heterocyclic ring or a heteroaromatic ring. The so-called “pyridazine” is not even a pyridazine, but multiple other core structures, as R6 and R7, together with the atoms to which they are attached, form a 5-6 membered cyclic hydrocarbon, a 5-6 membered heterocyclic ring or 5-6 membered heteroaryl that is optionally substituted with one or more substituents. R8 can further add multiple varied rings to the structure (see, e.g. claim 58). As a single non-limiting example, see e.g. compound 40 (Applicant’s elected species).
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Further, the specification provides no support that the pyridazine containing compounds inhibit NLRP3 activity. To the extent that there is any biological testing in the specification, it solely shows inhibiting of IL-1 beta, and does not specifically link it to the NLRP3 inflammasome, as there are other cellular targets beyond NLRP3, which can inhibit IL-1 beta.
On searching, the elected species was found to be free of art, and the search was expanded across the breadth of the claims. Accordingly, the election of species requirement is withdrawn with respect to the compounds.
For the foregoing reasons, the election of species is maintained. The restriction/ election requirement is hereby MADE FINAL. Claims 1, 5, 6, 13, 14, 50, 55, 56, 59-61, 63 and 65-68 are pending, and have been examined herewith to the extent of Applicant’s elected species of a disease.
Priority
Applicant has claimed foreign priority to the following applications:
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-12/25/2025 to CN20201156271.X (“‘CN ‘271X”)- Applicant is not accorded foreign priority to this application. See, e.g. the definition of R4 and R5 in CN ‘271-X:
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Compare to the definition of R4 and R5 in the instant application:
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-01/22/2021 to CN 202110090687.2 (“’CN 687.2”)- Applicant is not accorded foreign priority to this application. See, e.g. the definition of R4 and R5 in ‘CN 687.2, which are similarly defined as above.
-02/08/2021 to CN 202110172665.0 (“CN ‘665-0”)- Applicant is not accorded foreign priority to this application. No English language translation copy is of record. However, the foreign language copy as to R4 and R5 has a first line reference to “5-6”, which is consistent with the language of the earlier referenced above foreign applications, regarding a “5- to 6-membered cyclic hydrocarbon”.
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-05/28/2021 to CN 202110592769.7 (“CN 769.7”)- Applicant is not accorded foreign priority to this application. No English language translation copy is of record. However, the foreign language copy as to R4 and R5 has a first line reference to “5-6”, which is consistent with the language of the earlier referenced above foreign applications, regarding a “5- to 6-membered cyclic hydrocarbon”.
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-07/13/2021 to CN202110791592.3 (“CN 592.3”)- Applicant is not accorded foreign priority to this application. No English language translation copy is of record. However, the foreign language copy as to R4 and R5 has a first line reference to “5-6”, which is consistent with the language of the earlier referenced above foreign applications, regarding a “5- to 6-membered cyclic hydrocarbon”.
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Accordingly, the priority date accorded to the instant application is its filing date, which is 12/07/2023.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 63 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 63 is directed to a method for preventing and/ or treating inflammasome- related diseases. The claim term “inflammasome- related diseases” is vague and ambiguous and subject to many different interpretations. It is not a term of art, and it is not defined in the specification either. To the extent that there is a reference to it, the specification simply lumps together the large group of diseases of claim 63- inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases- into a single long sentence of no definition whatsoever of which is which, and with further large genuses of diseases of vastly different etiology and pathology. Specifically, paragraph [0216] of the specification provides: “The inflammasome-related disease, the immune disease, the inflammatory disease, the autoimmune disease and/or the autoinflammatory disease may be specifically selected from the group consisting of: autoinflammatory fever syndromes (such as cryo-pyrin-associated periodic syndromes), sickle-cell anemia, systemic lupus erythematosus, liver-related diseases (such as chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis, alcoholic steatohepatitis and alcoholic liver disease), inflammatory arthritis-related diseases (such as gout, chondrocalcinosis, osteoarthritis, rheumatoid arthritis and acute or chronic arthritis), kidney-related diseases (such as hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis-associated inflammation, type I or type II diabetes and complications thereof (such as nephropathy and retinopathy)), neuroinflammation-related diseases (such as brain infection, acute injury, multiple sclerosis, Alzheimer's disease and neurodegenerative diseases), cardiovascular and metabolic disorders or diseases (such as cardiovascular risk reduction (CvRR), atherosclerosis, type I and type II diabetes and related complications, peripheral artery disease (PAD), acute heart failure and hypertension), wound healing, scar formation, inflammatory skin diseases (e.g., acne and hidradenitis suppurativa), asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases/conditions (e.g., myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis, lung cancer and colon cancer).” Further, Applicant itself, in response to the restriction/ election requirement requesting the election of a single species of a disease according to claim 63, failed to designate one such species, and responded in a circular manner electing the entire genus of “inflammasome- related diseases”. The specification further fails to disclose any single disease, of any kind, being either treated or prevented. To the extent that there is any biological testing, it merely assesses in vitro inhibitory effect of IL-1beta on human monocytes of compounds according to the invention. (Example 1). Further, although the heading to Example 1 purports to relate to “assays for inhibitory activity against NLRP3 inflammasomes in human monocytes” nowhere is the data on IL-1beta inhibition linked anywhere to inhibitory activity against NLRP3 inflammasomes. This is further pertinent, given that the NLRP3 inflammasome is not the only pathway that can inhibit IL-1 beta. IL-1 beta signaling can be blocked at multiple points, e.g. downstream of NLRP3 by a direct block of IL-1 beta itself, by blocking other inflammasomes that process IL-1 beta, by inhibiting the signals that activate NLRP3 (e.g. ROS), by other anti-inflammatory strategies, which modulate IL-1 beta (e.g. NF-kB), etc. Either way, the effect on IL-1 beta is not correlated at all to any prevention or treatment of any inflammasome-related disease.
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.
Claim 63 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 inhibiting IL-1 beta in human monocytes with a compound or the pharmaceutically acceptable salt thereof according to claim 1, does not reasonably provide enablement for a method for preventing and/or treating inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases in a patient which comprises administering to the patient a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to claim 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. ‘
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1, 2) The nature of the invention and the breadth of the claims
Claim 63 is directed to a method for preventing and/or treating inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases in a patient which comprises administering to the patient a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to claim 1.
The claim is very broad with respect to both the compounds claimed in claim 1, as well as the diseases claimed. The specification provides that these claim terms refer to large genuses of diseases of vastly different etiology and pathology. Specifically, paragraph [0216] of the specification provides: “The inflammasome-related disease, the immune disease, the inflammatory disease, the autoimmune disease and/or the autoinflammatory disease may be specifically selected from the group consisting of: autoinflammatory fever syndromes (such as cryo-pyrin-associated periodic syndromes), sickle-cell anemia, systemic lupus erythematosus, liver-related diseases (such as chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis, alcoholic steatohepatitis and alcoholic liver disease), inflammatory arthritis-related diseases (such as gout, chondrocalcinosis, osteoarthritis, rheumatoid arthritis and acute or chronic arthritis), kidney-related diseases (such as hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis-associated inflammation, type I or type II diabetes and complications thereof (such as nephropathy and retinopathy)), neuroinflammation-related diseases (such as brain infection, acute injury, multiple sclerosis, Alzheimer's disease and neurodegenerative diseases), cardiovascular and metabolic disorders or diseases (such as cardiovascular risk reduction (CvRR), atherosclerosis, type I and type II diabetes and related complications, peripheral artery disease (PAD), acute heart failure and hypertension), wound healing, scar formation, inflammatory skin diseases (e.g., acne and hidradenitis suppurativa), asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases/conditions (e.g., myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis, lung cancer and colon cancer).”
(3, 4) The state of the prior art and predictability and unpredictability of the art
A broad review of the literature discloses that there isn’t any drug known in the art for treating or preventing such a broad array of diseases of vastly different etiology and pathology. Further, there is no known cure for a number of the recited diseases, e.g. neurodegenerative diseases, multiple sclerosis, etc.
Li et al., Inflammasomes as therapeutic targets in human diseases, Signal Transduction and Targeted Therapy volume 6, Article number: 247 (2021) (“Li”) is used as indicative of state of the art on inflammasomes as therapeutic targets in human diseases. Li discloses that not only NLRP3 generates IL-1 beta, but so do other inflammasomes as well. “The canonical inflammasomes (NLRP3, NLRC4, and AIM2) serve as a platform to engage pro-caspase-1 (Figs. 1–3 and Box 1), which becomes active caspase-1 through the oligomerization of pro-caspase-1 proteins.7 Activated caspase-1 processes pro-interleukin-1β (IL-1β) and pro-IL-18 to generate their active forms, which induce pyroptosis, a pro-inflammatory form of cell death.2,8,9,10”
Li notes in the section “Roles of inflammasomes in sterile inflammatory diseases” that: “The inflammasome is a double-edged sword in various diseases, especially in sterile inflammatory diseases, and the outcomes can be either good or bad depending on the disease, and the genetic background.” As one example, it notes the role of inflammasomes in cancer. “Chronic inflammation mediated by inflammasomes plays a central role in tumorigenesis by altering the microenvironment and leading to neoangiogenesis, the proliferation of tumor cells, and metastasis. However, under certain conditions, inflammasome signaling also inhibits tumor growth by maintaining intestinal barrier integrity.124,125”
In Conclusions and Perspectives, Li finally provides: “In summary, NLRP3 acts as a nodal factor which can be beneficial after either activation or inhibition. Aberrant NLRP3 activation is implicated in chronic inflammation that leads to the development of cancer, aging, and degenerative diseases. IL-1 blockers such as canakinumab, anakinra, and rilonacept are only effective in treating certain NLRP3-mediated diseases. The development of more effective treatment relies on a thorough understanding of the signaling pathways triggering the activation of the inflammasome (Box 2). In addition, a better understanding the mechanisms underlying the regulation of non-canonical inflammasome responses and the interaction between the non-canonical inflammasome and the canonical inflammasome may lead to the development of effective therapies for a broader range of pathological conditions.”
(5) The relative skill of those in the art
The relative level of skill possessed by one of ordinary skill in the art of pharmaceutical compositions and methods of disease treatment is relatively high, as a majority of lead investigators directing scientific research and development in this particular technological area possess a Ph.D. or M.D. in a scientific discipline such as medicinal chemistry, biochemistry, pharmacology, biology or the like.
(6, 7, 8) The amount of direction or guidance presented; the presence or absence of working examples; and the quantity of experimentation necessary.
The specification fails to provide any scientific data and working embodiments whatsoever with respect to a method for preventing and/or treating inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases in a patient. The specification further fails to disclose any single disease, of any kind, being either treated or prevented. To the extent that there is any biological testing, it merely assesses in vitro inhibitory effect of IL-1beta on human monocytes of compounds according to the invention. (Example 1). Further, although the heading to Example 1 purports to relate to “assays for inhibitory activity against NLRP3 inflammasomes in human monocytes” nowhere is the data on IL-1beta inhibition linked anywhere to inhibitory activity against NLRP3 inflammasomes. This is further pertinent, given that the NLRP3 inflammasome is not the only pathway that can inhibit IL-1 beta. IL-1 beta signaling can be blocked at multiple points, e.g. downstream of NLRP3 by a direct block of IL-1 beta itself, by blocking other inflammasomes that process IL-1 beta, by inhibiting the signals that activate NLRP3 (e.g. ROS), by other anti-inflammatory strategies, which modulate IL-1 beta (e.g. NF-kB), etc. Either way, the effect on IL-1 beta is not correlated at all to any prevention or treatment of any inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases in a patient. As such, one of skill in the art would need to conduct undue experimentation to test if any such method exists.
Genentech states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.” Genentech v. Novo Nordisk, 108 F.3d 1361, 1366 (Fed. Cir. 1997).
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, 5, 6, 13, 14, 49, 50-52, 55, 60, 61, 63 and 65-68 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by WO 2023278438 A1 to Collins et al. (“Collins”; of record).
Collins relates to NLRP3 modulators for preventing or treating useful for the treatment of NLRP3 associated diseases including, but not limited to, type 2 diabetes, atherosclerosis, obesity and gout. ([0002], [0087], [0095]). It discloses that the NLRP3 inflammasome is a critical component of the innate immune response and inflammatory process, and its aberrant activity is pathogenic in inherited disorders such as cryopyrin-associated periodic syndromes (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer’s disease and atherosclerosis. Per Collins, current treatments for NLRP3 -related diseases include biologic agents that target IL-1. ([0002]).
Collins discloses compounds of Formula (Ij)
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This discloses a pyridine structure, wherein, per Applicant’s Formula I, and noting for illustration some, not all, overlapping ingredients:
-R6 and R7, together with the atoms to which they are attached, form a 5- membered cyclic hydrocarbon, with one or more substituents selected from the group consisting of: halogen, C1-6 alkyl
-Z is O, -NH-(CH2)n where n is 0-2
-R8 is (5-10 membered) heterocyclyl that is optionally substituted with one or more substituents selected from hydrogen, halogen,
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, wherein R10a and R10b are C3-4 alkyl
-R1 is halogen, OH
-R2 and R3, together with the atoms to which they are attached, form a 5-6 membered cyclic hydrocarbon (aka cyclopentyl or cyclohexyl), heterocyclic ring, or heteroaryl ring
-R4 and R5 are independently selected from the group consisting of H, halogen.
(claim 1).
Collins further discloses that the compounds can exist in their isotopically-labeled forms, e.g. with substitution with heavy isotopes such as deuterium. ([00179]).
Collins further discloses a pharmaceutical composition comprising a compound of any one of claims 1-101, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
Allowable subject matter
Claims 56, 59 and 66 are rejected as dependent on a rejected base claim, but would be allowable if written in independent claim format.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SVETLANA M IVANOVA whose telephone number is (571)270-3277. The examiner can normally be reached 8:30-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney L. Klinkel can be reached at (571) 270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SVETLANA M IVANOVA/ Primary Examiner, Art Unit 1627
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