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 .
Status
This is a Final Office Action is in response to the August 21, 2025 Amendment and Request for Reconsideration After Non-Final Action.
Claims 1, 12-14 and 16-26 pending and under examination, claims 1, 12, 13, 16, 19 and 21-22 are amended, claims 23-26 are newly added and claims 2-11 and 15 are cancelled in the above-identified application.
Priority
U.S. Pat. Appln. Ser. No. 17/592,779, Filed: February 4, 2022, is a continuation (i.e., “bypass continuation”) of WO 2021/026451 A1 (i.e., PCT/US2020/045402 Appln.) Intern.’l Filing Date: August 7, 2020, which claims priority from U.S. Prov. Appln. Ser. No. 62/884,457, Filed: August 8, 2019.
Information Disclosure Statement
An Information Disclosure Statements (IDS), on August 21, 2025, are compliance with the provisions of 37 CFR 1.97.
Accordingly, Information Disclosure Statements have been considered by the Examiner.
Withdrawn Rejections/Objections
Applicants are notified that any outstanding rejection(s) or objection(s), respectively, not expressly maintained in this office action now are withdrawn or rendered moot in view of Applicants amendments and/or remarks of record.
Based on Applicants August 21, 2025 Amendment and Reconsideration After Non-Final Rejection and corresponding claim amendments, the following information is acknowledged, objections and/or rejections are withdrawn or rendered moot:
[1] Applicants arguments directed to original election of:
Group (a) directed to a compound of Formula IV or a salt solvate, N-oxide or prodrug thereof defines the aliphatic group to include straight chain alkyls and cycloalkyls; (i.e., e.g., inc. cyclohexyl);
such that elected compound species VI-176 (i.e., which was searched previously) includes and reads on claim 8:
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claims 1 and 12-14, 16 and 22-36 (i.e., 24-26 newly added) read on the elected species; and
an IRAK inhibitor remains an elected species as it reads on claims 16 and 18.
Therefore this restriction is considered proper and FINAL.
[2] Rejection of claims 1 and 19-22 (withdrawn per amendment) and claims 9, 10, 15 (cancelled) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd para. for reasons of record are moot;
[3] Rejection of claims 1, and 12-22 under 35 U.S.C. 102(a)(1) as being anticipated by and/or rendered obvious in light of WO 2016/172560 A1 to Rigel Pharmaceuticals, Inc. (Intern.’l Pub. Date: October 27, 2016, Intern.’l Filing Date: April 22, 2016). (“WO ‘560 Appln.”) is withdrawn (i.e. see new Rejections necessitated by Amendment).;
[4] Rejection of claims 12 and 13 under 35 U.S.C. § 102(a)(1) as being anticipated by WO 2016/172560 (560 publication) is withdrawn; and
[5] Non-statutory obviousness-type double patenting rejection of Claims 1, 2, 8-10 and 12-22 as being unpatentable over claims 1 to 26 of U.S. Pat. No. 10,941,140 to Li et al. (Rigel Pharmaceuticals, Inc.), Filed: June 18, 2019, Issued: March 9, 2021 (“U.S. ‘140 Pat.”) is rendered moot.
MAINTAINED REJECTIONS
Maintained previous rejections of record may include:
deletion of rejections obviated by claim amendments
new issues raised by amendment (i.e., in bold text as necessitated by Applicants’ arguments) and/or corresponding clarifying statements in bold text (i.e., where such. clarifying statements which do not substantively change original rejection and notes that claims 2-11 and 15 now cancelled); and
will be discussed in the order of significance to facilitate prosecution.
[A] Maintained Rejection under 35 U.S.C. 112(a)
Amended claims 1-2 and 12-22, respectively are rejected under 35 U.S.C. 112(a), because the specification, while enabling for:
A method for treating cytokine release syndrome (CRS), which comprises administering a therapeutically effective amount of a compound of Formula (VII):
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to a patient in need thereof;
DOES NOT reasonably provide enablement for:
A Method:
for preventing or that prevent a symptom of cytokine release syndrome (CRS) (i.e., as in claim 1 and corresponding claims); or
which requires administration of a 1st therapy and/or further comprising administration of a 2nd therapeutic agent;
where the aforementioned method:
comprises administering:
ALL compound(s) to ameliorate(s) ALL sign(s) or symptom(s) of (or associated with) CRS (i.e., when only fever is identified in claim 1)
compared to
the severity of ALL sign(s) or ALL symptom(s) of (or associated with) CRS (i.e., when only fever is identified in claim 1),prior to administration of compound of Formula (VII) (i.e., as in claim 14);
ANY or ALL compound(s) to a subject that has previously been administered A or ALL first therapy(ies) for which CRS is ANY or ALL known, suspected, or potential side effect(s); or
ANY or ALL compound(s) to a to a subject who will be, or is concurrently being, administered ANY or ALL first therapies for which CRS is a known, suspected, or potential side effect(s) (i.e., as in claim 16);
where the first therapy comprises:
ANY or ALL cell therapies (i.e., as in claim 17);
which comprise(s) ANY or ALL chimeric antigen receptor (CAR)-expressing therapy, ANY or ALL transgenic receptor therapies, or ANY or ALL combination thereof. (i.e., as in claim 18);
ANY or ALL compound(s) further comprises administering ANY or ALL second therapeutic agent(s) selected from the group consisting of ANY or ALL: analgesic(s), antibiotic, anticoagulant(s), antibody(ies), ANY or ALL anti-inflammatory agent(s), immunosuppressant(s), A guanylate cyclase-C agonist(s), intestinal secretagogue(s), antiviral(s), anticancer(s), antifungal(s), and a combination(s) thereof (i.e., as in claim 19),
which [is selected from] ANY or ALL steroid(s), anti-inflammatory agent(s), immunosuppressant(s), or combination(s) thereof. (i.e., as in claim 20); i.e., selected from
i.e., as defined in claim 21 below:
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where the second therapeutic is dexamethasone, prednisone, or a combination thereof.
ANY or ALL second therapeutic(s) is or selected from ANY or ALL:
corticosteroid(s), an alkylating agent(s), a calcineurin inhibitor(s), an inhibitor(s) of inosine monophosphate dehydrogenase (IMPDH), an agent(s) designed to suppress cellular immunity while leaving the recipient's humoral immunologic response intact, or a combination(s) thereof.
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 the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the application coupled with information known in the art without undue experimentation. (United States v. Teletronics Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based on a single factor, but rather a conclusion reached by weighing many factors (See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988).
These factors include the following:
Nature Of The Invention.
The nature of this invention relates generally to:
A method for treating cytokine release syndrome (CRS), which comprises administering a therapeutically effective amount of a compound of Formula (VII):
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;
a pharmaceutically acceptable salt to a to a patient in need thereof;
where the claimed invention teaches:
also corresponding pharmaceutical compositions;
the aforementioned compounds are identified as IRAK or JAK inhibitors;
also Includes corresponding pharmaceutical compositions; and
there is only one (1) in vitro assay testing 2 selected compounds of the instant specification, where one of the aforementioned compounds demonstrated inhibitory activity against IRAK and the other against JAK proteins; and
there were NO examples in the specification teaching:
an administration of compounds of the present invention where a subject will be or is concurrently administered another or a “first therapy”, which may be used in conjunction with other therapies (i.e., e.g.,, defined as first therapy);
administration of a second therapeutic agent as defined from an extensive list of conventionally art known agents for treatment of various diseases (i.e., as defined in the instant specification)
Scope of Breath Of The Claims.
The scope of the amended claims involves:
A method for treating cytokine release syndrome (CRS), which comprises administering a therapeutically effective amount of a compound of Formula (IV); or
a pharmaceutically acceptable salt to a to a patient in need thereof;
Thus, the scope of claims is very broad.
The breadth of the claims are broad, because it encompasses: in vitro and in vivo contexts in both treatment and treating cytokine release syndrome and associated diseases, i.e., as defined in the specification with vastly different causes, progress, known or unknown etiologies or unknown etiologies or pathologies beyond those in the claimed invention.
3 & 4) State of the Art and Predictability In The Art.
The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification.
In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling (i.e., see MPEP 2164.03)
The invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally
considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is a reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F.2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F.2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F.2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657. Conventional art taught that:
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Amount Of Guidance Provided By Applicants.
Applicants provide guidance in the detailed specification disclosure, which describes methods, procedures, and parameters for making and using a compound of the claimed invention, i.e., which only provides screening assay against CRS Inhibitor Assay where it is known in the art that IL-6 is a key driver of inflammatory cascade in CRS, its inhibition is a primary therapeutic strategy and that both IL-2 and IL-6 are released during CRS and contribute to the inflammatory response.as shown below:
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; and
where:
the above assay measures in vitro inhibitory/cytotoxicity activity of 4 representative compounds, i.e., e.g.,
two (2) known compounds tofacitinib & acalabrutinib; and two (2) compounds from the instant invention, a compound Formula (IV) and compound VI-176 (i.e., where this compound is an interleukin receptor associate kinase (IRAK) inhibitor having same chemical structural core structure, where RC2 = cyclohexyl, but is distinguished from the current elected species, where RC2 = straight chain hetero aliphatic and RC2 ≠ cyclohexyl) and Formula (IA) (i.e., identified as I-432); and
the assay data appears to show that :
the specific compound VI-176, is a potent (IRAK) inhibitor that inhibits the IRAK-1/4 proteins as indicated by the low EC50 value (i.e., requiring less concentration to achieve the same effect);
where the conventional art teaches that research targeting IRAK-1/4 with inhibitors is being investigated as a potential therapeutic strategy for managing CRS and other inflammatory disorders (i.e., inhibition of IRAK-1/4 is thought to reduce production of inflammatory cytokines and mitigate the severity of CRS; (i.e., e.g., see teaching ref. generally: Garcia-Manero et al., “R289, a Dual Irak 1/4 Inhibitor, in Patients with Relapsed/Refractory (R/R) Lower-Risk Myelodysplastic Syndrome (LR-MDS): Initial Results from a Phase 1b Study”, Blood, (2024), Vol. 144, Issue Supp 1. 4595-4596)
Number Of Working Examples.
[A] Working examples in the instant specification demonstrate the practicality of the claimed invention, which include detailed written description in the instant specification of:
Compound of Formula (I) or pharmaceutically acceptable salts thereof, i.e., which includes:
compounds of Formula IV are set forth in List 2: Exemplary Ccompounds identified as V-1 to V-156 and VI-1 to VI-180 are found in the specification at page 35, col. 2 starting at [0879] to page 43, col. 1 ending at [1125]; and
corresponding written preparation compound examples, I.e., e.g., see col. 1, at page 81 starting at [1456] to col. 2, page 94, ending at [1553],
which may exemplify corresponding pharmaceutical salt forms and/or intermediates with detailed experimentals for making those compounds with characterization data, , etc.; and
assessment of pharmacological/biological activity of those compounds include:
Example 4 directed to a compound in vitro screening assay using dendritic cells to test for inhibition of CRS activity with a single IRAK compound VI-176 of the claimed invention, there was NO other testing of any of the other compounds taught in the present invention.
Other than those two (2) aforementioned compounds showing inhibition in the aforementioned assay, the instant specification teaches NO WORKING EXAMPLES directed to:
methods preventing or that prevent a symptom of cytokine release syndrome (CRS) (i.e., as in claim 1 and corresponding claims), which comprises administration of:
a 1st therapy;
where the first therapy comprises ANY or ALL cell therapies (i.e., as in claim 17), comprised of an chimeric antigen receptor (CAR)-expressing therapy, transgenic receptor therapies, or combinations thereof. (i.e., as in claim 18 or in specification);and/or
further comprising administration of
a 2nd therapeutic agent;
where ANY or ALL compound(s) further comprises administering ANY or ALL second therapeutic agent(s) selected from the group consisting of ANY or ALL: analgesic(s), antibiotic, anticoagulant(s), antibody(ies), ANY or ALL anti-inflammatory agent(s), immunosuppressant(s), A guanylate cyclase-C agonist(s), intestinal secretagogue(s), antiviral(s), anticancer(s), antifungal(s), and a combination(s) thereof (i.e., as in claim 19),
which [is selected from] ANY or ALL steroid(s), anti-inflammatory agent(s), immunosuppressant(s), or combination(s) thereof. (i.e., as in claim 20); i.e., selected from i.e., as defined in claim 21 below:
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; or dexamethasone, prednisone, or a combination thereof.
Regarding noted above, these cannot be simply willed into existence. As was stated in Morton International Inc. v. Cardinal Chemical Co., 28 USPQ2d 1190 “The specification purports to teach, with over fifty examples, the preparation of the claimed compounds with the required connectivity. However,...there is no evidence that such compounds exist...the examples of the '881 patent do not produce the postulated compounds...there is...no evidence that such compounds even exist.”
The same circumstance appears to be true here. Hence, Applicants must show that the scope of claimed compounds and other requirements yields all the desired effects of scope claimed, other than those exemplified by the limited Experimental Example section of the present invention, where examples can be made/ used for the stated purpose in all situations across the board, not just in animals, but also in human subjects or limit the claims accordingly.
Level Of Skill In The Art (High)
An ordinary artisan in the area of drug development would have experience in screening chemical compounds for particular activities. Screening of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target, (i.e., receptor, protein, enzyme, etc.) is well known. Additionally, while high throughput screening assays can often be employed, developing a therapeutic method, as claimed, is generally not well-known or routine, given the complexity of certain biological systems.
MPEP §2164.01 (a) states, "A conclusion of lack of enablement means that, based on the evidence regarding each of the above 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 scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." That conclusion is clearly justified here that Applicant is not enabled for making these compounds or compositions or treating the diseases mentioned.
Appropriate action, which include claim amendments to delete non-enabled and/or subject matter not exemplified or supported by specification is required accordingly.
[B] Maintained Rejections under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA )
Claims 14 and 16-22 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd para. for 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.
Claims 14 to 22 are rejected for lacking clarity and for being indefinite, vague and , ambiguous, such that it is unclear what the metes and bounds of the claimed invention are. In particular:
In claim 14, how does one determine after administering a compound, the disease is “ameliorated” or even what constitutes “a sign or symptom of CRS”, compared how and what specific conditions before, during and after are “to the severity of the sign or symptom prior to administration of the compound”.
Claims 16 to 18, respectively are vague, ambiguous and indefinite as the metes and bounds of the claims are unclear, i.e., e.g.:
how is it determined whether “a subject [was] previously be administered a first therapy” and what that first therapy is?; and
more importantly what are the CRS terms, criterion for administration and which subjects are chosen for treatment, i.e., e.g.:
“for which CRS is a known, suspected, or potential side effect” or
“administering to a subject who will be, or is concurrently being, administered a first therapy”.
what is “the first therapy”; what type of “cell therapy” it is (i.e., as per claim 17); i.e., where defined types of cell therapy therein selected from “chimeric antigen receptor (CAR)-expressing therapy, a transgenic receptor therapy, or a combination thereof”, which also represent broad sub-categories of cell therapy types that may be further defined (i.e., as per claim18) .
Appropriate correction is requested accordingly.
[C] Maintained Non-Statutory Double Patent Rejection(s)
Non-statutory double patent (“NSDP”)rejection of:
the instant application over co-pending U.S. Appln. Ser. No. 18/690,705 to Markovtsov et al. is maintained and reiterated below in its entirety as NO claims have been found allowable at this time;
the Office is aware that under MPEP Section 804, subsection 1.B.1(b), that:
if provisional NSDP rejections is/are the only remaining rejections in an application, (i.e., filing date of instant WO Appln. PCT/US2020/045402, August 7, 2020 is earlier than the patent term filing date (excluding the benefit under 35 U.S.C. § 119) of the 371 US ’705 Appln. (U.S. 371 Nat ’l. Stage of PCT/US2022/041718, Filed :August 26, 2022).
Reiterated NSDP Rejection
[B] Claims 1, 2, 8-10 and 12-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 and 15-32 of co-pending U.S. Appln. Ser. No. 18/690,705 to Markovtsov et al. (Rigel Pharmaceuticals, Inc.) Filed: March 8, 2024 (“U.S. ‘705 Appln.”; i.e., 371 Appln. Date, which corresponds to U.S. Pat. Appln. Pub. No.: 2024/0382470 A1, Pub. Date: November 21, 2024).
Although the conflicting claims are not identical, they are not patentably distinct from each other because:
[1] method claims 1-2, 8-10 and 12-22 of the instant invention, which comprises administering compounds of Formula (IV) or pharmaceutically acceptable salts thereof (i.e., which are identified as Janus Kinases (JAK) and/or Interleukin Receptor-Associated Kinase (IRAK) inhibitors) and corresponding pharmaceutical compositions
(i.e., where: Formula (IV) therein defines RC2 ≠ cycloalkyl or substituted cycloalkyl,
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RC10 is H, aliphatic, alkoxy, heteroaliphatic, carboxyl ester, araliphatic, NO2, CN, OH, haloalkyl, acyl, alkyl phosphate or alkylphosphonate)
overlaps with:
[2] method claims 1-8 and 15-32 of the U.S. ‘705 Appln. (reference application), which comprises administering compounds of Formula (IV) or pharmaceutically acceptable salts thereof (i.e., which are identified as interleukin receptor-associated kinase (IRAK) inhibitors) and corresponding pharmaceutical compositions.
This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014), the court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a non-statutory double patenting context. See also Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008);Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003).
Here, one skilled in the art would recognize that the aforementioned issued patent is directed to the use of the identical compositions comprised of the identical compounds for treatment methods, which administer compounds and/or pharmaceutical compositions overlap with and/or are recited in both the instant application and U.S. ‘705 Appln (i.e., see specification and claims therein).
In the instant scenario, the U.S. ‘705 Appln is directed to a treatment methods, using a compound of Formula (IV) or a pharmaceutically acceptable salt thereof, corresponding pharmaceutical compositions and corresponding specific compound species that fall within the scope of the claimed invention:
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the aforementioned issued patent is directed to the use chemical compounds or pharmaceutically acceptable salts thereof, which are IRAK inhibitors, with a common chemical core ring structure with overlapping functional group moieties and/or corresponding pharmaceutical compositions, respectively used in treatment methods directed to diseases which operate by a common mechanism of action via an inter-related network for treating cytokine release syndrome, related diseases and/or disorders.
The ordinary artisan would recognize as obvious that determination of whether “said compounds were present in the prior art,” is implicit in the patented claim in view of Sun Pharmaceutical Industries, LTD. v. Eli Lilly and Company which states the following: “Similarly, in Pfizer, the earlier patent claimed several compounds and the specification disclosed their use in treating inflammation and inflammation-associated disorders. 518 F.3d at 1363 & n.9; see U.S. Patent No. SUN PHARMACEUTICAL v. ELI LILLY 85,563,165 (“’165 patent”), at [57], col.1 11.11-14, col.3 11.3-27. The later patent then claimed a method of using these compounds for treating inflammation, inflammation-associated disorders, and specific inflammation-associated disorders, including arthritis, pain, and fever. Pfizer, 518 F.3d at 1363 & n.9; see U.S. Patent No. 5,760,068 (“’068 patent”) col.97 1.49- col. 108 1.29. After rejecting the patentee’s objection to our consideration of the specification of the earlier patent, we determined that the later patent “merely claims a particular use described in the [earlier] patent of the claimed compositions of the [earlier] patent.” Pfizer, 518 F.3d at 1363 & n.8. As such, we concluded that the asserted claims of the later patent were not “patentably distinct” from the claims of the earlier patent, and thus the later patent was invalid for obviousness-type double patenting. Id. at 1368.
A non-statutory obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); and In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985).
Obviousness-type double patenting requires rejection of an application claim when the claimed subject matter is not patentably distinct from the subject matter claimed in a commonly owned patent, or a non-commonly owned patent but subject to a joint research agreement as set forth in 35 U.S.C.103 (c)(2) and (3), when the issuance of a second patent would provide unjustified extension of the term of the right to exclude granted by a patent. See Eli Lilly & Co. v. Barr Labs., Inc., 251 F.3d 955, 58 USPQ2d 1869 (Fed. Cir. 2001); Ex parte Davis, 56 USPQ2d 1434, 1435-36 (Bd. Pat. App. & Inter. 2000).
One having ordinary skill in the art at the time of the invention would have noted that subject matter exists in both the instant invention and the that is not patentably distinct from each other. It has also been held that a prior art disclosed genus of useful compounds is sufficient to render prima facie obvious a species falling within a genus. In re Susi, 440 F.2d 442, 169 USPQ 423, 425 (CCPA 1971), followed by the Federal Circuit in Merck & Co. v. Biocraft Laboratories, 847 F.2d 804, 10 USPQ 2d 1843, 1846 (Fed. Cir. 1989).
Applicants are requested to provide clarification, and appropriate action is required accordingly in this matter.
NEW REJECTIONS NECESSITATED BY AMENDMENT
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 16 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd para., 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 16 is rejected for lack of clarity, indefiniteness and for failure to define exactly when or how it is determined that:
a subject “previously been administered a first therapy” for which CRS is “a known, suspected, or potential side effect”; i.e., e.g., how is it determined that a subject was previously administered a first therapy” and what are specific signs and/or associated factors to clearly define what constitutes “suspected or potential side effects” symptoms and risks associated with the aforementioned disease. Without clear definitions in this regard the metes and bounds of the claimed invention are indeterminate.
Appropriate clarification is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
WO 2016/172560 A1 to Rigel Pharmaceuticals, Inc. (Intern.’l Pub. Date: October 27, 2016, Intern.’l Filing Date: April 22, 2016). (“WO ‘560 Appln.”), alone, in combination with and/or further in view of, alone, in combination with and/or further in view of:
Wang et al., “IRAK-4 Inhibitors for Inflammation”, Curr Top Med Chem., 2009 May; 9(8):724–737. doi:10.2174/156802609789044407, esp. at page 725, col. 1 para. 2; and
Cushing et al., “IRAK4 Kinase Activity Controls Toll-Like Receptor–Induced Inflammation Through The Transcription Factor IRF5 In Primary Human Monocytes”, J Biol Chem. 2017 Sep 18;292(45):18689–18698. doi: 10.1074/jbc.M117.796912 (i.e., see Fig. 5 and Discussion therein)
Claimed Invention
The present invention is directed to:
amended claim 1 and corresponding claims 12-26 now are directed to
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where the specification teaches that:
that compounds of the present invention, such as the species above is an IRAK inhibitor, such as IRAK1, IRAK2, IRAK3 and/or IRAK4 inhibitors.(i.e., see [0107]); and/or
Janus Kinases (JAK) and/or Interleukin Receptor-Associated Kinase (IRAK) pathways, and/or may be kinase inhibitors, including, but not limited to, JAK inhibitors, such as JAK1, JAK2, JAK3 and/or JAK4 inhibitors; and/or
methods also comprise administering such compound(S) to a subject;
who is has received, is currently receiving a first and second therapeutic agent, and/or will be receiving a cell therapy.
The Prior Art
In general, the WO ‘560 A1 Appln. discloses and teaches:
generally novel interleukin receptor associated kinases (IRAK) inhibitors and corresponding compositions, preparation methods, which are used to treat or prevent an IRAK-associated disease or condition.
specifically IRAK inhibitor and/or JAK inhibitor compounds with a genus that encompasses and a species identical to that of the present invention
useful for treating, which is an inflammatory condition.
methods of using pyrazole compounds, which are interleukin receptor associated kinases (IRAK) inhibitors, which comprise a compound of
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or a salt thereof
including other specific embodiments (i.e. where Het-1 includes pyrazole) ; and
specifically teaches the elected compound species of the claimed invention shown below
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such compounds and/or compositions may be used to treat or prevent an IRAK-associated disease or conditions that include:
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(i.e., see page 16, lines 31-37 to page 17, lines 1-3)
In light of the above:
the present invention claims a method of treating cytokine release syndrome (CRS) using identical IRAK or JAK inhibitor compounds (i.e., common pyrazole core compound structure genus and same compound species);
It was well-known in the art, prior to the earliest effective filing date of August 8, 2019, that both IRAK and JAK signaling pathways are integral components of the broader inflammatory signaling cascade and are involved in the modulation of cytokine production. which discusses the role of these pathways in inflammation, and which describes the state of knowledge regarding inflammatory signaling and potential therapeutic targets at the time); i.e., as supported by the following teaches:
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CRS is a serious side effect of certain immunotherapies, and its management often involves concurrent treatments to mitigate inflammation and organ dysfunction and other symptoms, i.e., where patients that develop grade CRS toxicity after being treated develop related symptoms e.g. such as fever or hypotension. (i.e., e.g., see Murthy et al., “Cytokine Release Syndrome: Current Perspectives”, Immunotargets Ther. 2019 Oct 29;8:43–52. doi: 10.2147/ITT.S202015; and Shimabukuro-Vornhagen et al. Journal for ImmunoTherapy of Cancer (2018) 6:56 https://doi.org/10.1186/s40425-018-0343-9); and
That the method may further comprise administering a second therapeutic agent, i.e., e.g., which includes, a steroid, an anti-viral, an anti-inflammatory agent, an immunosuppressant, or a combination thereof; i.e., e.g.,
where:
The steroid may be a corticosteroid, such as, for example, dexamethasone or prednisone, or a combination thereof.
compounds taught therein also may be used combination with other therapeutic agents useful for the disorder or condition being treated. These compounds may be administered simultaneously, sequentially in any order, by the same route of administration, or by a different route. . . . the second therapeutic agent is . . . . an immunosuppressant . . . steroid or a nonsteroidal anti-inflammatory agent
for information regarding this section, secondary agents and/or therapies; i.e., e.g., see WO ‘560 Appln. Section on “Combinations of Therapeutic Agents” at page 77, lines 28-37 to page 80, lines 1-4.
Based on the foregoing and the teachings of the art, the ordinary artisan in administering pyrazole compound IRAK inhibitors in methods of treatment for cytokine release syndrome would meet with a reasonable expectation of success, because:
cytokine release syndrome treatment methods described in the claimed invention and WO ‘560 Appln., respectively, administer compounds that share a common pyrazole compound core genus and corresponding compound species, respectively, which are also identified as IRAK inhibitors in the specification that:
which teaches that:
“pyrazole compounds, methods of making the compounds, and methods of using the compounds. In one embodiment the disclosed compounds are tyrosine kinase inhibitors. . . [where such] . . compounds useful in blocking one or more cytokine signaling pathways, such as the IL-17 signaling pathway. . . [these] pyrazole compounds are useful for treating conditions in which inhibition of an interleukin-1 receptor-associated kinase (IRAK) pathway is therapeutically useful. In some embodiments, the compounds directly inhibit an IRAK protein, such as IRAK1, IRAK2, IRAK3 or IRAK4.
would operate via the same mechanism of action that involves blocking the activity of IRAK4, which plays a crucial role in inflammatory signaling pathways and its downstream signaling;
This is further supported by Applicants’ admission in the instant application, where the record states:
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IRAK compounds taught in the WO ‘560 Appln. and the claimed invention:
demonstrated biological activity via different screening assays (i.e., e.g., tested for cytotoxicity in the claimed invention).; and
compounds taught therein may be used alone, in combination with one another, or as an adjunct to, or in combination with, a second therapeutic agent and other established therapies.
One of ordinary skill in the art (PHOSITA) at the time of the invention, upon reading and considering the established scientific understanding of inflammatory signaling pathways, would have been motivated to use the disclosed IRAK/JAK inhibitors to treat other inflammatory conditions, including CRS, which is a known manifestation of excessive cytokine release.
The PHOSITA would have had a reasonable expectation of success in using these inhibitors to manage CRS, given the known mechanism of action of the compounds (IRAK/JAK inhibition) and the known biological target of the disease (cytokine signaling pathways). The application of a known compound to a condition sharing the same underlying mechanism already identified as a target for that compound in the prior art is an obvious variation.
The claimed invention, therefore, merely represents the application of a known treatment to a known condition within the same established field of inflammatory disease treatment, which would have been obvious to a PHOSITA.
One of ordinary skill in the art would have been motivated in in administering IRAK inhibitors for treatment for cytokine release syndrome, because there remains an urgent unmet medical need to eliminate this life threatening condition characterized by overactivation of signaling molecules by regulating an immune response leading to increased cytokine release, i.e., may be due triggered as a side effect to miscellaneous immunotherapies, transplants, monoclonal antibody infusions, bone marrow transplants, etc. and/or caused by severe infections, autoimmune diseases etc.
Based on the foregoing, claimed invention is rendered obvious over WO ‘880 Appln alone, in view of or in combination with the Wang and Cushing references.
Therefore, the claimed invention is anticipated by and/or rendered obvious over the WO ‘560 Appln, alone, in view of or in combination with cited references.
CONCLUSION
Applicants amendment necessitated the new ground(s) of rejection presented in this Office action. There will be no rejoinder and examination of withdrawn claims in the instant matter. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to GRACE C HSU whose telephone number is (571) 270-1689. The Examiner can normally be reached Monday-Friday 7:30 am - 6 pm.
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/G.C.H./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624