DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims and Response to Amendments
Claims 1, 2, 8, 9, 11, 12, and 19-36 are pending. Claims 3-7, 10, and 13-18 are cancelled.
Status of Priority
The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/CN2020/107028, filed on August 5, 2020. This application also claims the benefits of foreign priority to CN201910721525.7, filed on August 6, 2019.
Specification - Disclosure
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Withdrawn Rejections
Applicant is notified that any outstanding rejection or objection that is not expressly maintained in this office action has been withdrawn or rendered moot in view of applicant’s amendments and/or remarks.
Claim Objections
Claim 8 is objected to because of the following informalities:
Claim 8 recites the following compounds:
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However, as currently presented, it is unclear what atom is bonded to the cyclopropyl ring (see circled region).
Please provide a clearer structure of instant compounds EXP-5 and EXP-6.
Also, please add a period after the structure of EXP-13.
Appropriate correction is required.
Examiner’s note on novelty and nonobviousness
The closest prior art is:
Menet et al. (Menet) (WO2010010190A1; published January 28, 2010).
Novelty:
Menet teaches [1,2,4]triazolo[1,5-a]pyridine compounds represented by formula (I) (herein, referred to as Menet-formula-I):
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as JAK inhibitors that are useful for the treatment of degenerative and inflammatory diseases (title, abstract, and para. 0001). The variables of Menet-formula-I are defined in claim 1 of Menet. The JAK inhibitors represented by Menet-formula-I (specifically, examples disclosed on pg. 115-194) differ from those presently claimed in that all the compounds of Menet do not have Cy1 = a thiophene moiety.
Thus, the instant invention is considered novel.
Nonobviousness:
Both Menet and the present invention disclose JAK inhibitors. Although a POSITA would have considered it obvious to further explore derivatives of the compounds disclosed in Menet (such as the compounds of the present invention) as JAK inhibitors, Menet does not teach nor suggest Cy1 of Menet-formula-I to be specifically a thiophene moiety to arrive at the instantly claimed compounds.
For example, compound 200 of Menet has the following structure (pg. 160):
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and instant compound EXP-1 has the following structure
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(instant specification, pg. 5)
The only structural difference between the two compounds is that the instant compound EXP-1 replaces the phenyl linker present in compound 200 of Menet with a thiophene moiety. Although Menet states in claim 1 that Cy1 (which corresponds to phenyl in compound 200 of Menet) may be an aryl or heteroaryl (which includes a thiophene moiety), Menet does not teach nor suggest that a POSITA would have been motivated to specifically select thiophene over the numerous other disclosed aryl and heteroaryl groups to achieve the improved and unexpected results demonstrated in the instant specification.
Thus, the instant invention is considered nonobvious.
Claim Rejections - 35 USC § 112(a)
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.
Written Description
Claims 19-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Currently, the claims are very broad insofar as they encompass methods of treating any disease that is JAK kinase-related, without restricting the claimed methods to particular diseases or classes of diseases. However, the instant specification only demonstrates that the instant compounds have JAK1, JAK2, JAK3, and TYK2 inhibitory activity in a biochemical assay (see pg. 41 of the instant specification – clean copy [dated 12/01/2025]). In terms of in vivo experimentation, the instant specification only provides a working example of instant compound EXP-3 in a rat model of collagen-induced arthritis (CIA) to assess the compound’s efficacy in treating arthritis in rats (Embodiment 18: Pharmacodynamics model in vivo starting on pg. 48). The test results show that a 10 mg/kg dose of EXP-3 (administered for two weeks) has the strongest effect on reducing swelling of the extremities of the rat subjects (pg. 51, Table 11). According to the prior art, CIA is an established experimental model of human rheumatoid arthritis (RA) as the CIA model is “suitable for studying the alterations of immune functions during [RA] disease development and progression” (Richter, J. et al. Collagen-induced arthritis: severity and immune response attenuation using multivalent N-acetyl glucosamine. Clinical and Experimental Immunology 2014, 177, 121–133.; pg. 122, left col., 2nd paragraph). Based on these teachings, instant compound EXP-3 will have utility for treating RA.
The instant specification also reports of tests that were run to detect the instant compounds’ proliferation inhibitory activity on HeLa cells (Embodiment 12-1, starting on pg. 42), BaF3 cells (Embodiment 12-2, starting on pg. 43), and THP1 cells (Embodiment 12-3, starting on pg. 44).
According to the prior art:
Fragoulis et al. (Fragoulis, G. E. et al. JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis. Rheumatology 2019, 58, i43-i54.; published February 26, 2019.)
Note:This is supporting article 3 cited by Applicant (see pg. 11 of Applicant Remarks dated 06/29/2026).
Fragoulis teaches the following:
“The value of different Janus kinase inhibitors’ specificities across disease states remains to be defined” (pg. i43, in the box titled “Rheumatology key messages,” 2nd bullet point).
This teaching demonstrates that the therapeutic activity of JAK inhibitors across different disease states is unpredictable and had not been fully established in the art.
“Although the focus of JAK inhibitors for the treatment of chronic inflammatory conditions has been on RA [i.e., rheumatoid arthritis], there are other conditions in which JAKinibs [i.e., JAK inhibitors] could serve as therapeutic options” (pg. i43, introduction section, 2nd paragraph, 3rd to last sentence).
Fragoulis characterizes JAK inhibitors only as compounds that could serve as therapeutic options for other conditions, rather than teaching that efficacy in rheumatoid arthritis necessarily translates to efficacy in other JAK kinase-related diseases. Thus, the instant specification’s demonstration that EXP-3 is effective in collage-induced arthritis also does not necessarily translates to all of the instant compounds exhibiting therapeutic efficacy in all other JAK kinase-related diseases.
“The efficacy and safety profiles of JAKinibs have not always corresponded with the effects predicted based on our understanding of the JAK/STAT pathways and selectivity of these drugs” (pg. i50, “Future perspectives and conclusion” section, 4th sentence).
This teaching expressly demonstrates that knowledge of JAK/STAT pathway involvement and JAK inhibitor selectivity was insufficient to reliably predict therapeutic efficacy across different JAK kinase-related diseases. Accordingly, the instant specification’s demonstration of JAK inhibitory activity and efficacy in limited disease models is insufficient to reliably predict therapeutic efficacy across all JAK kinase-related diseases.
According to another prior art:
Kahl et al. (Kahl) (Kahl, L. et al. Safety, tolerability, efficacy and pharmacodynamics of the selective JAK1 inhibitor GSK2586184 in patients with systemic lupus erythematosus. Lupus 2016, 25, 1420-1430.)
Kahl discloses the following:
Goal of the study:
“to evaluate the pharmacodynamics, efficacy, safety and tolerability of the JAK1 inhibitor GSK2586184 in adults with systemic lupus erythematosus (SLE)” (abstract, 1st sentence).
GSK2586184 description:
Structure:
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“GSK2586184 (GLPG0788), generically known as solcitinib, is an orally active, competitive, potent, selective JAK1 inhibitor that was evaluated for treatment of inflammatory and auto-immune diseases. GSK2586184 has demonstrated selective JAK1 inhibition in preclinical and human in vitro enzyme, cellular and tissue assay systems and was well tolerated in healthy volunteers (GSK, data on file) and patients with psoriasis” (pg. 1421, left col., 1st full paragraph).
“At interim analysis, GSK2586184 showed no significant effect on mean interferon transcriptional biomarker expression (all panels). The study was declared futile and recruitment was halted at 50 patients” (abstract).
“Shortly thereafter, significant safety data were identified, including elevated liver enzymes in six patients (one confirmed and one suspected case of Drug Reaction with Eosinophilia and Systemic Symptoms), leading to immediate dosing cessation” (abstract).
“Taken together, these data indicate that the risk-benefit of treatment with this experimental JAK-1 inhibitor does not support further clinical development for treatment of lupus” (pg. 1429, Discussion section, last sentence).
In other words, Kahl teaches that even though GSK2586184 has demonstrated selective JAK1 inhibition in preclinical and human in vitro enzyme, cellular and tissue assay systems and was well tolerated in healthy volunteers and patients with psoriasis, it was not shown to be a clinically viable treatment for all JAK-related diseases: in this case, SLE.
The prior art further teaches:
Flamant et al. (Flamant) (Flamant, M. et al. Advances in the Development of Janus Kinase Inhibitors in Inflammatory Bowel Disease: Future Prospects. Drugs 2017, 77, 1057-1068.)
Flamant teaches that tofacitinib (i.e., a JAK1/3 inhibitor) was clinically evaluated for both Crohn’s disease (CD) and ulcerative colitis (UC). Clinical development for Crohn’s disease was subsequently discontinued, whereas development for ulcerative colitis progressed to phase 3 clinical trials (see Table 1 of Flamant for summary):
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(note: IBD = inflammatory bowel disease)
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.
In both the initial phase II study and the larger phase IIb induction and maintenance studies, treatment with tofacitinib did not produce statistically significant improvements in clinical remission or clinical response compared with placebo (pg. 1063, 2nd to last paragraph of left col., and the paragraph that bridges between the left and right col.). Although the drug demonstrated an acceptable safety and tolerability profile (pg. 1063, right col., 1st full paragraph, 1st sentence), its efficacy in Crohn’s disease was substantially lower than that observed in ulcerative colitis (UC) (pg. 1063, paragraph that bridges between the left and right col.). Because the clinical trials failed to demonstrate statistically significant efficacy compared with placebo, Pfizer announced that it would not proceed with phase 3 clinical development of tofacitinib for Crohn’s disease (pg. 1063, paragraph that bridges between the left and right col., last sentence).
In other words, Flamant teaches that therapeutic efficacy of tofacitinib is disease-dependent. Although effective for ulcerative colitis, tofacitinib failed to demonstrate statistically significant therapeutic efficacy in Crohn’s disease.
Taking all the above into account, the instant specification does not reasonably convey to one of ordinary skill in the art that the inventor(s) were in possession, as of the effective filing date, of the claimed methods of treating any JAK kinase-related diseases as recited in instant claims 19-24.
Recall: the working examples do establish that the claimed compounds inhibit JAK1, JAK2, JAK3, and TYK2 in biochemical assays and that instant compound EXP-3 demonstrates therapeutic activity in a rat collagen-induced arthritis model (an established model of rheumatoid arthritis in humans). The instant specification additionally reports proliferation-inhibition testing in HeLa, BaF3, and THP-1 cells. However, these limited examples are not representative of the extensive and biologically diverse genus of JAK kinase-related diseases encompassed by instant claims 19-24.
This deficiency is particularly significant because the state of the art demonstrates that therapeutic efficacy of JAK inhibitors across different diseases was unpredictable. Fragoulis expressly teaches that “the value of different Janus kinase inhibitors’ specificities across diseases states remains to be defined” and further teaches that the efficacy and safety profiles of JAK inhibitors have not always corresponded with effects predicted from knowledge of JAK/STAT pathway and drug selectivity. Consistent with this unpredictability, Kahl demonstrates that solcitinib, despite having demonstrated selective JAK1 inhibitory activity, was not show to be a clinically viable treatment for systemic lupus erythematosus, while Flamant demonstrates that tofacitinib was effective for ulcerative colitis but failed to demonstrate statistically significant therapeutic efficacy in Crohn’s disease. Thus, the state of the art demonstrates that JAK inhibitory activity, alone (in vitro and in vivo), does not establish possession of methods of treating every disease associated with JAK.
Accordingly, the limited disclosure of JAK inhibitory activity, a single collagen-induced arthritis animal model, and proliferation assays in a limited number of cell lines do not provide a representative number of species commensurate with the breadth and biological diversity of the claimed genus.
According to MPEP § 2163:
“Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’ Such correlations may be established ‘by the inventor as described in the specification,’ or they may be ‘known in the art at the time of the filing date.’ See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).
In the instant case, the specification does demonstrate possession of the treatment methods disclosed in instant claims 25-36, but does not reasonably convey possession of the substantially broader genus encompassing treatment of any JAK kinase-related disease. Therefore, the instant specification fails to provide adequate written description support for the full scope of the claimed invention.
Furthermore, the recitation of “JAK kinase-related diseases” creates a “reach-through” aspect to the claim. Specifically, the claim is not limited to diseases presently recognized as JAK kinase-related, but, instead, potentially reaches through to diseases whose relationship to JAK kinase may only be discovered or established through future scientific investigation. In the instant case, the specification does not demonstrate possession of methods of treating diseases whose association with JAK kinase was unknown or unrecognized at the time of filing, nor does it provide representative disclosure sufficient to show possession of such subsequently identified members of the claimed genus. Accordingly, the “reach-through” scope of the claim further demonstrates that the instant specification does not reasonably convey possession of the full scope of “JAK kinase-related diseases” as presently claimed.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 19-24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The limitation “JAK kinase-related disease” renders the scope of the claims indefinite because the claim defines the disease only by its functional relationship to JAK kinase, without identifying which diseases are encompassed or providing an objective standard for determining when a disease is sufficiently “related” to JAK kinase to fall within the scope of the claim. It is therefore unclear whether the limitation only encompasses diseases that were established to be directly driven by JAK kinase activity as of the effective filing date, or does it also encompass diseases that may subsequently be discovered or later determined to involve JAK kinase signaling. It is further unclear whether the limitation encompasses diseases in which JAK signaling contributes to pathogenesis or does the limitation encompass any disease for which JAK inhibition produces some biological or therapeutic effect. Moreover, the claim does not provide an objective standard for determining what degree of therapeutic effect is sufficient for a disease to be considered “JAK kinase-related,” thereby rendering the boundaries of the claimed genus to be vague and indefinite.
Allowable Subject Matter
Claims 1, 2, 9, 11, 25, 26, 28, 29, 31, 32, 34, and 35 are allowed. Claim 8 is objected to but would be allowable once the appropriate corrections are made. Claims 12, 27, 30, 33, and 36 are also objected to for depending on claim 8 which is objected to. Claims 12, 27, 30, 33, and 36 would be allowable once the appropriate corrections are made to instant claim 8.
Conclusion
Claims 1, 2, 9, 11, 25, 26, 28, 29, 31, 32, 34, and 35 are allowed. Claims 8, 12, 27, 30, 33, and 36 are objected to. Claims 19-24 are rejected. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTEN ROMERO whose telephone number is (571)272-6478. The examiner can normally be reached M-F 9:30 AM - 6:00 PM ET.
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/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624
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