DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application, filed on 06/23/2022, claims priority to U.S. Application No. 63/213,943 filed on 06/23/2021.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/29/2024 has been entered.
DETAILED ACTION
The Amendments and Applicant’s Arguments submitted on 11/07/2025 have been received and
its contents have been carefully considered.
Claim 16 was amended, claims 1, 3, 6-7 were canceled, and claims 2, and 4-5 were previously canceled. Claims 8-18 are pending with claims 8-15 and 17-18 were previously withdrawn and claim 16 is under consideration.
Withdrawn Claim Rejection - 35 USC § 103
Rejection of claims 1, 3, and 6-7 under 35 U.S.C. 103 as being unpatentable over G. Shipps et al. (WO 2008/153701 A1, 12/18/2008), is withdrawn in view of applicant amendment submitted on 11/07/2025, that rejected claims 1, 3, and 6-7.
Rejection Maintained
Claim Rejections - 35 USC § 112(a) (Scope of Enablement)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claim 16 remain rejected under 35 U.S.C. 112(a) because the specification, while enabling one of skill in the art to make and use:
1. A method for treating a disease or disorder mediated by NLRP3 in a subject, comprising administering an effective amount of a compound of claim 16 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient to the subject, wherein the disease or disorder is selected from a group consisting of asthma, sarcoidosis, age-related macular degeneration, chronic liver disease, viral hepatitis, non- alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, alcoholic liver disease, gout, pseudogout, osteoarthritis, rheumatoid arthritis, arthropathy, hyperoxaluria, lupus nephritis, hypertensive nephropathy, hypertension, atherosclerosis, type I and type II diabetes, peripheral artery disease (PAD), cryopyrin-associated periodic syndrome, nephropathy, retinopathy.1
does not reasonably enable one of skill in the art to make and use the full scope of the claimed method.
Factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue” include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
MPEP. § 2164.01(a); In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988); In re Wright, 999 F.2d 1557, 27 USPQ2d 1510 (Fed. Cir. 1993).
Breadth of the Claims
The claim breadth is vast in view of the generic nature of the claimed method. Claim 16 is directed to genera that encompass at least tens of thousands of compounds. Claim 16 encompass an extremely large number of diseases/disorders. Significantly, the full claim breadth of treatable diseases of claim 16 cannot be ascertained because neither the art of record nor the instant specification teaches methods or models to determine the full scope of diseases/conditions embraced by “disorder mediated by NLRP3” due to the nascent nature of the art (see discussion of State of the Art – Predictability” below.
Considering the genus of “inflammasome-related diseases” per claim 16, inflammation is a complex process involving multiple immune cell types and the inflammatory response is a key characteristic of many human diseases. Inflammatory diseases include acute disorders such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), as well as chronic disorders such as cancer and arteriosclerosis. C. Evans et al., Frontiers in Pharmacology, 1-2 (2021). In another example, Shen teaches some of NLRP3 inflammasome related diseases. H Shen et al., 17 Autoimmunity Reviews, 694-702 (2018) (“Shen”). Shen however teaches that although the pathogenesis and etiology research on these diseases is advancing, as well as continuous progress on treatment, the long-term prognoses are unsatisfactory for most patients. Shen at page 695, col. 2. Shen further teaches that the mechanism leading to NLRP3 inflammasome activation is still debated and unresolved. Shen at page 699, col. 2. In another example, the claim directed to “cancer related diseases or disorders. The specification does not define a meaning of the phrase “cancer related diseases or disorders” or provide definition of what are these diseases and disorders. The instant specification at [0042] recites that “NLRP3 has also been implicated in the pathogenesis of many cancers”, and provide example of these cancers such as lung cancer, AML, glioma, and explicitly recites “role for the NLRP3 inflammasome has been suggested in the carcinogenesis of various other cancers. Cancer is not a single disease, or a cluster of closely related disorders. There are hundreds of proliferative diseases, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain, and salivary glands. They can occur in every part of the body. Therefore, the scope of the diseases covered is deemed very broad, and cannot be considered enabled by the instant specification.
The prior art knows that there never has been a compound capable of treating cancers generally. “The cancer therapy art remains highly unpredictable, and no example exists for efficacy of a single product against tumors generally.” A similar statement appears at In re Application of Hozumi et al., 226 USPQ 353: “In spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer. Cancer is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way”. There are compounds that treat a modest range of cancers, but no one has ever been able to determine how to get a compound to be effective against cancer generally, or even a majority of cancers. This also applied to, for example, to cardiovascular diseases or disorders and metabolic diseases or disorders. In sum, the claim is extremely broad with respect to both compounds claimed and diseases treated.
State of the Art -- Predictability
The claim is directed to treatment of a disease or disorder mediated by NLRP3, particularly treatment of inflammasome-related diseases or disorders. See e.g., R. Sharma et al., 22 Nature Immunology, 550-559 (2021) (stating that overall, it is critical to continue to improve our mechanistic understanding of NLRP3 and its divergent functions across diseases; Sharma at page 556, col. 2).
This art is nascent and unpredictable. For example, S. Paik et al., Cellular & Molecular Biology, 1141-1160 (2021) (“Paik”) teaches that respecting NLRP3 inflammasome activation many questions remain, e.g., how the individual and/or multiple PTM regulation is curated for licensing of the NLRP3 inflammasome, how different NLRP3 stimuli are engaged to converge into the signaling cascades that lead to full activation of the NLRP3 inflammasome, and which signaling pathway(s) play key roles in the ultimate assembly of the inflammasome complex. Paik at page 1155, col. 1. Paik teaches that further work is needed to clarify the molecular mechanisms of NLRP3 inflammasome activation. Id. Paik teaches that a wide range of small molecules/reagents are being developed for the regulation of NLRP3 inflammasome activation, although therapeutic outcomes have been limited in terms of clinical trials. Id. Paik teaches that future work may provide a comprehensive interpretation of the highly regulated nature of the formation and activation of the NLRP3 inflammasome complex. Id. Paik teaches that these efforts will be critical for the future development of potential therapeutic and preventive agents for NLRP3-related diseases. Id.
A discussion of each of the numerous claimed diseases cannot be accomplished here. However, even with respect to cancer generally (lung cancer), S. Hamarsheh et al., 11 frontiers in Immunology, 1-11 (2021) (“Hamarsheh”) teaches that despite the well-characterized crucial functions for NLRP3 inflammasome in the immune system, their roles in cancer remain rather complicated and elusive. Hamarsheh at page 8, col. 1. Hamarsheh teaches that the double-edged sword effect of NLRP3 inflammasome in cancer appears to be dependent on several factors, including its levels of expression, downstream effector molecules (i.e., IL-1b or IL-18), cancer type, stages of tumorigenesis as well as the potential presence of mutations affecting NLRP3 expression. Id. Therefore, in order to further understand these roles, future research needs to address several points: (i) driving factors of NLRP3 inflammasome activation in tumors, such as oncogenic mutations or mutations of inflammasome components, (ii) possible cross-talk pathways and molecules interacting and affecting the regulation of NLRP3 inflammasome, (iii) effects of TME and its components on NLRP3 inflammasome activation and vice versa, (iv) effect. Id.
In view of the foregoing, the state of the art is found to be unpredictable. A further significant factor is that the claim is directed to a nascent technology. MPEP § 2164.03 (citing Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) “[n]ascent technology, however, must be enabled with a ‘specific and useful teaching.’ The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee’s instruction”).
Guidance in the Specification and Working Examples
In Example 1, the specification discloses testing by way of an NLRP3 inflammasome assay using human promonocytic leukemia THP-1 cells for a single claimed compound (i.e., RS-D7). Specification at page 46-47, Example 1. The specification teaches that in this assay, the NLRP3 inflammasome cells are activated triggering a series of downstream events, including the activation of caspase-1 and the subsequent conversion of pro-IL-I[Symbol font/0x62] to pro-inflammatory cytokine IL-I[Symbol font/0x62]. Specification at page 46-47, [0091]. The specification teaches that treatment with RS-D7 showed dose-dependent inhibition of caspase-1 and IL-I[Symbol font/0x62].
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The specification speculates that since no individual protein was inhibited by RS-D7, the RS-D7 may inhibit the process of NLRP3 inflammasome assembly from driving a reduction in IL- I[Symbol font/0x62]. Specification at page 47, [0093].
In Example 2, the specification teaches that male TgM83 mice were dosed with RS-D7 30 mg/kg (PO) or control. Specification at page 48. The treated mice were tested for motor coordination and motor skill learning. Specification at page 49, [0099]; Id. at page 50, [00102]. Compared to the WT control, TgM83 mice exhibited hypolocomotion activity by 6,080 cm moved in the given time of one hour, and oral gavage of 30 mg/kg RS-D7 could significantly rescue the hypolocomotion observed by increasing 5,007 cm of distance moved in the given time (all P < 0.05). Specification at page 49, [00103]. In addition, oral gavage of 30 mg/kg RS-D7 significantly ameliorated the motor coordination deficits by prolonging the falling latency to 76.8 seconds (all P < 0.05). Specification at page 49, [00104].
Tissues samples were also taken to characterize the inflammatory response after RS-D7 treatment and the level of inflammatory cytokines measured. Specification at page 48, [00100]; Id. at pages 50-51, [00105]. The specification teaches that a significant difference was found in the inflammation cytokines from TgM83 mice; that is an oral gavage of 30 mg/kg RS-D7 significantly inhibits the overexpression of IL-1[Symbol font/0x62], IL-6, and TNF-[Symbol font/0x61] in TgM83 mice.
In summary, the specification discloses working examples, where only one compound of the claimed genus (RS-D7) was shown to have in vitro and in vivo (TgM83 mice) inflammatory properties and that RS-D7 could significantly rescue the hypolocomotion and ameliorate the motor coordination deficits in TgM83 mice.
Neither the instant specification nor the art of record teaches one of skill in the art how to identify the full scope of diseases or disorders mediated by NPLR3. Further, neither the art of record nor the instant specification teaches a general model for determining whether a particular disorder is mediated by NPLR3.
Further Applicant discloses no structure activity relationships regarding which compounds of the large chemical genus one of ordinary skill in the art should select to treat particular diseases/disorders.
Still further, the specification does not disclose a single example of a claimed “solvate” nor give any guidance as to which chemical structure is required to meet the requirements of “solvate”. Nor does the art of record appear to supplement Applicant’s disclosure. Routine searches conducted did not identify any validated solvates structurally related to the claimed compounds.
The Quantity of Experimentation Needed Is Undue
In the current case, claim 16 is properly rejected under 35 U.S.C. § 112(a), for lack of enablement because upon weighing the above-discussed factors, the specification at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full claim scope without undue experimentation. The primary Wands factor considered are the claim breadth, unpredictability, and lack of guidance in the specification and art of record. A further significant factor is that the claim is directed a nascent technology as evidenced by the discussion above. MPEP § 2164.03 (citing Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) “[n]ascent technology, however, must be enabled with a ‘specific and useful teaching.’ The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee’s instruction”).
The primary issue with respect to the § 112 rejection is as follows. The specification provides specific guidance only with respect to one example compound (i.e., RS-D7). This lack of guidance is balanced with the art’s nascent nature and unpredictability. For example, as discussed above, S. Paik et al., Cellular & Molecular Biology, 1141-1160 (2021) (“Paik”) teaches that respecting NLRP3 inflammasome activation many questions remain. This lack of guidance and unpredictably is further considered in light of the vast claim breadth. In view of balancing the above-discussed factors, a prima facie case of undue experimentation is established.
The facts here are more egregious than the facts in Idenix Pharms. LLC v. Gilead Scis. Inc., 941 F.3d 1149, 1161 (Fed. Cir. 2019). In Idenix, the claim recited a method of treating HCV (in this opinion one disease) by administering a broad genus of nucleoside compounds having a specific chemical structure. Idenix, 941 F.3d at 1154. The Idenix court found that the only working examples were exceedingly narrow relative to the claim scope. Idenix at 1161. The Idenix court found that “at least many, many thousands” of potential compounds met the structural requirements of the claim, and their synthesis was routine. Id. at 1157, 1160. Nevertheless, each of the compounds “would need to be screened in order to know whether or not they are effective against HCV.” Id. at 1162. The Idenix court stated that where “practicing the full scope of the claim would have required excessive experimentation, even if routine, the patent is invalid for lack of enablement.” Id. at 1163 (citation omitted). Thus, in view of the quantity of experimentation required (even though the techniques were routine), the lack of meaningful guidance or working examples across the full scope of the claim, and the immense breadth of screening required to determine which claimed compounds are effective against HCV, the Idenix court found undue experimentation. Id. at 1162. Furthermore, where, as here, “working examples are present but are ‘very narrow, despite the wide breadth of the claim at issue,’ this factor weighs against enablement.” Idenix Pharms. LLC v. Gilead Scis. Inc., 941 F.3d 1149, 1161 (Fed. Cir. 2019) (quoting Enzo Biochem, Inc. v. Calgene, Inc., 188 F.3d 1362, 1374 (Fed. Cir. 1999)).
Response to Arguments
Applicant argues:
Furthermore, some additional diseases and disorders have been included: inflammatory diseases, auto-immune diseases, auto-inflammatory diseases, liver related diseases or disorders, kidney related diseases, cardiovascular or metabolic diseases or disorders, inflammatory skin diseases, wound healing and scar formation, autoinflammatory fever syndromes, hemodialysis related inflammation, acute heart failure, hidradenitis suppurativa, acne, lung cancer, myeloprolferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis, multiple system atrophy (MSA), dementia with Lewy bodies, traumatic brain injury (TBI). The "predictability or lack thereof' in the art refers to the ability of one skilled in the art to extrapolate the disclosed or known results to the claimed invention. If one skilled in the art can readily anticipate the effect of a change within the subject matter to which the claimed invention pertains, then there is predictability in the art. See MPEP 2164.03. The additional diseases and disorders listed above have been proved associated with NLRP3, as evident in the exemplary publications listed below. Accordingly, the skilled artisan would readily appreciate that the compound of the present disclosure can be used to treat those diseases and disorders. The Applicant respectfully submits that the present disclosure enables the list of diseases and disorders described in the pending claim 16.
Examiner response:
Applicant's arguments filed have been fully considered but they are not persuasive because the breadth of claim 16 is vast in view of the instant specification.
However, it does not enable one of ordinary skill in the art to make and use the full scope of the claimed method. The. The connection between NLRP3 and the claimed diseases and disorders is not yet established. Shen teaches that the mechanism leading to NLRP3 inflammasome activation is still debated and unresolved. Please see the Breadth of claims and predictability above. Claim 16 compounds (46 compounds) for treating an extremely large number of diseases/disorders. Significantly, the full claim breadth of treatable diseases of claim 16 cannot be ascertained because neither the art of record nor the instant specification teaches methods or models to determine the full scope of diseases/conditions embraced by “disorder mediated by NLRP3” due to the nascent nature of the art (see discussion of State of the Art – Predictability, above). For example, the amended claim 16 recites “lung cancer”, however,
the instant specification does not provide guidance to one of ordinary skill in the art to treat this complex condition. Claim 16 recites 46 compound with distinct structure, and diseases and conditions are mechanistically and symptomatically diverse. One of ordinary skill in the art needs to know which compound from the list of claim 16 of is active, the type of disease or condition, the method of treatment, effective amount, administration protocol and the treatment regimen, which makes the amount of experimentation required by one of skill in the art to practice the full claim scope to be unduly burdensome. Applicant argues that inhibiting NLRP3 would treat the claimed diseases and disorders, however, as discussed above and according to Sharma and Paik, NLRP3 nature and its formation and activation complex is highly regulated which will be critical for the future development of potential therapeutic and preventive agents for NLRP3-related diseases. As such, the state of the art is unpredictable, and that the claim is directed a nascent technology.
Applicant provides exemplary publications to support enablement of the above listed disease and conditions, however, Applicant does not provide copies of these publications.
Rejection Maintained/Slightly Modified
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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.
Claim 16 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by G. Scaramuzzino, EP1336602A1, 08/20/2003, “Scaramuzzino” cited in the PTO-892 dated 05/30/2024).
Scaramuzzino discloses compound (RXII) below for prevention and treatment of inflammatory, ischemic, degenerative and proliferative diseases of musculoskeletal, tegumental, respiratory, gastrointestinal, genito-urinary and central nervous systems, [Scaramuzzino, Abstract, and pg. 2, 0006], wherein the prevention and treatment include rheumatoid arthritis, osteoarthritis, lupus, osteoporosis, asthma, lung tumors, hepatic cirrhosis, colon-rectum tumors, multiple sclerosis, etc. [Scaramuzzino, pg. 3, 0027]:
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[Scaramuzzino, pg. 52, 2nd comp.].
Scaramuzzino’s compound (RXII) above recited as the first compound in claim 16 as (RS-D7: 5-O-Desmethyl-Omeprazole). Therefore, Scaramuzzino anticipates claim 16.
Response to Arguments
Applicant argues:
the prior pending claims 1, 3, and 6-7 are canceled without prejudice. The Applicant respectfully submits that the rejections are moot.
Examiner response:
The amended claim 16 is now rejected under Scaramuzzino, because Scaramuzzino discloses RS-D7: 5-0-Desmethyl-Omeprazole for treating rheumatoid arthritis, osteoarthritis, lupus, osteoporosis, asthma, lung tumors.
Conclusion
Claim 16 is rejected. No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/M.M.A./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
1 Searches were conducted to determine art-known connection between a claimed disease and NLRP3. Upon balancing and art-known connection between activation and inhibition of NLRP3 and disease mechanism with the predictability in the art and guidance in the specification (particularly the working examples, discussed in detail below, demonstrating the connection between RS-D7 (a compound of claim 16) and mediation of NLRP3), it is considered that one of skill in the art could practice this subject matter, upon the filing date of the instant application, without undue experimentation. MPEP § 2164.02; In re Brana, 51 F.3d 1560, 1566, 34 USPQ2d 1436, 1441 (Fed. Cir. 1995).