DETAILED ACTION
This office action is in response to applicant’s filing dated January 26, 2024.
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 of Claims
Claims 1-10 are pending in the instant application. Acknowledgement is made of Applicant's amendments filed January 26, 2024.
Priority
The present application is a 371 of PCT/CN2022/071491 filed on January 12, 2022, which claims benefit of foreign priority to CHINA 202110048366.6 filed on January 14, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on January 11, 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
Acknowledgement is made of the drawings received on July 11, 2023. These drawings are accepted.
Specification
The disclosure is objected to because of the following informalities:
The specification recites the abbreviation AIA (page 10, line 15 and page 20, lines 1, 23, and 25). In a review of the specification, the unabbreviated version was not identified. It is improper to use abbreviations unless said abbreviation is used in combination with the unabbreviated version in the first instance in which it appears.
The Examiner notes that the specification discloses AIA pharmacodynamic studies of the compounds of the present invention in rats; Experimental materials: Complete Freund’s adjuvant; and Scoring criteria: 0 point: no redness and swelling; 1 point: mild redness and swelling of ankle joints and wrist joints; 2 points: moderate redness and swelling of ankle joints and wrist joints; 3 points: severe redness and swelling of the paw including the fingertips; 4 points: maximal inflammation of the extremities, including multiple joints (see page 20). Thus, in view of the description of the experiment, AIA has been construed as adjuvant induced arthritis.
Appropriate correction is required.
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 9 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 9 recites the broad recitations “inflammation,” “autoimmune disease,” and “cancer” and the claim also recites
the inflammation is preferably selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, uveitis, psoriasis and atopic dermatitis
the autoimmune disease is preferably selected from the group consisting of multiple sclerosis and lupus
the cancer is preferably selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, mastoid nephroma, head and neck tumors, leukemia, lymphoma, myeloma and non-small cell lung cancer
which are the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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.
Claims 8 and 9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating rheumatoid arthritis comprising administering the compounds of instant claim 1, does not reasonably provide enablement for a method of treating or preventing a JAK1 and TYK2 activity related disease in a subject in need 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 use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
1. The nature of the invention, state and predictability of the art, and relative skill of those in the art
The invention relates to a method of treating or preventing any JAK1 and TYK2 activity related disease in a subject in need thereof.
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant’s invention would generally be a physician with a M.D. degree and several years of experience.
The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain).
As noted by claim 9, which depends from claim 8, a JAK1 and TYK2 activity related disease encompasses vastly different diseases with different etiology and pathophysiology. There are no known preventative treatments for any of the disorders listed in claim 9. Not only are the listed diseases extremely variable, developing therapies for those diseases is extremely unpredictable. For example, Dall’Era (Ann Rheum Dis, 2019; 78:729–735), cited for evidentiary purposes, teaches systemic lupus erythematosus (SLE) is a chronic autoimmune disease that follows a relapsing–remitting course; it is characterised by the production of autoantibodies against a range of autoantigens including nuclear components, immune-mediated inflammation in a variety of organs and the accrual of organ damage over time; despite its prevalence (approximately 70 cases per 100 000 people) and considerable impact on quality of life, treatment options remain inadequate, and the development of novel therapies has been slow (page 729, left, 1st paragraph). Dall’Era teaches only one new drug, belimumab, has been approved for the treatment of SLE in more than 60 years; while numerous other drugs and biologicals have entered clinical trials for SLE since the turn of the millennium, development of most has been halted at various stages; although some of these failures may be related to inefficacy of the investigational product or adverse events, there is general consensus in the community that problems with trial design and operation may have contributed to the unsuccessful outcomes (page 729, left, 2nd paragraph).
As illustrative of the state of the art of JAK1 and TYK2, the examiner cites Liu et al (Annals of the Rheumatic Diseases, 2020; 79:252); Gonciarz et al (Immunotherapy, 2021; 13(13):1135-1150); and Mortezavi et al (RMD open, 2022; 8(2):e002409 pp1-5).
Liu teaches Janus kinases (JAKs) are important regulators of intracellular responses triggered by many key proinflammatory cytokines and are clinically validated therapeutic targets for treating various autoimmune diseases; however, current approved JAK inhibitors failed to achieve maximal clinical benefit in part due to their unfavorable selectivity for individual JAKs such as JAK2 and/or JAK3, leading to dose-limiting toxicities or severe toxicities (e.g., thrombosis, anemia, immune suppression); selective inhibition of JAK1 and/or TYK2 may minimize or avoid some of the toxicities and potentially offer a better therapeutic window for treating autoimmune diseases; no highly selective JAK1/TYK2 inhibitor has been reported to date (Background).
Gonciarz teaches the process by which cytokines, growth factors and hormones influence cellular behavior is highly complex; in the human immune system, a central role in signal transduction and regulation is played by JAKs and STATs; the JAK/STAT pathway is critical to the effective operation of the immune system, with its diverse range of physiological activities; dysfunction of the JAK/STAT pathway is associated with autoimmune and inflammatory diseases; JAKs are associated with the intracellular components of transmembrane receptors for cytokines; in humans (in cells associated with the immune system) there are four JAKs: JAK1, JAK2, JAK3 and TYK2; pairs of these kinases are associated with each receptor and are required for signal transduction; TYK2 can pair with JAK1 or JAK2 (page 1135, 1st and 2nd paragraph). Gonciarz teaches the JAK/STAT signal transduction pathway mediates signals for over 50 ligands. This is achieved through the complexity of interactions between different JAK pairs and different STAT dimers (page 1135, last paragraph); the JAK/STAT system is highly regulated, with signal termination controlled by factors that include JAK dephosphorylation, production of inhibitory proteins and autoinhibition of JAK binding domains; thus, the response to cytokines in different cell types and at different times can be variable (page 1136, last paragraph). Gonciarz teaches no selective TYK2 inhibitor has yet been approved for clinical use and the published results from clinical trials are limited (page 1145, 2nd paragraph); small-molecule TYK2 inhibitors that are able to block IL-12, IL-23 and type 1 IFN (IFN-α and IFN-β) pathways may offer the potential to treat a broad spectrum of autoimmune/inflammatory diseases safely and more efficaciously; a significant challenge in this regard is attaining the desired level of TYK2 selectivity to avoid undesirable off-target effects (i.e., adequate target selectivity over other JAK kinases as well as against the broad class of kinases in general); despite the potential of TYK2 inhibition, identifying small molecules that selectively target the JH1 catalytically active site has proven challenging (page 1139).
Mortezavi teaches quite how each of the four JAK family members (JAK1, JAK2, JAK3 and TYK2) contributes to health and disease was unclear in the 1990s, and while incredible progress has been made over the past two decades, many important questions about JAK biology remain unanswered (page 1, left, 1st paragraph). Mortezavi teaches JAKs are enzymes, and JAK inhibitors generally work by competing with (adenosine triphosphate) ATP for the enzyme binding pocket; for JAK inhibitors that bind to the active site, the ATP binding pockets of JAK1/2/3 and TYK2 are structurally very similar, so designing a molecule that targets one member of the JAK family without blocking the others (i.e., true selectivity) has been quite challenging (page 1, right, 1st paragraph). Mortezavi teaches JAK inhibitors currently approved for use in rheumatology (tofacitinib, baricitinib, Upadacitinib and filgotinib) all potently inhibited JAK1; and of interest, there are now JAK inhibitors in development that selectively avoid JAK1 (page 2, left, 1st paragraph); in the preclinical phase (in vitro and animal models), data are generated to support the potential efficacy of the drug for the treatment of a disease state and potential adverse events based on the on-target and off-target actions of the drug; thus, the selectivity profile of a given JAK inhibitor, defined in the preclinical phase, can be used to generate hypotheses about the efficacy and the likely safety profile of the drug; however, this proposed profile remains hypothetical until the clinical phase of the drug development process begins (page 2, left, 3rd paragraph).
These articles plainly demonstrate that the art of developing and testing Jak1/Ty2 kinase inhibitor drugs, particularly for use in humans, is extremely unpredictable, particularly in the case of a single compound or genus of compounds being used to treat any and all any JAK1 and TYK2 activity related disease. If a compound is found to be useful for treating one JAK1 and TYK2 activity related disease, it would be extremely unpredictable to determine which other JAK1 and TYK2 activity related diseases would also be treatable with the same compound. If a compound is found to be useful for treating one autoimmune disorder, it would be extremely unpredictable to determine which other inflammatory or cell proliferative disorders would also be treatable with the same compound.
2. The breadth of the claims
Claims 8 and 9 are very broad in terms of the type of diseases being treated: all types of JAK1 and TYK2 activity related disease are claimed to be treated or prevented with a compound of claim 1.
3. The amount of direction or guidance provided and the presence or absence of working examples
The specification teaches Example 4, wherein compounds 1-a and 1-b are administered in Lewis rats injected with 0.1 mL of complete Freund’s adjuvant (AIA model, a known model of rheumatoid arthritis) (see page 20) and compounds 1-a and 1-b show significantly better efficacy than the reference compound (page 20 and Fig 1). Thus, the working examples do not provide sufficient written description support for the full scope of the claims.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that a compound of formula (I) could be predictably treat or prevent all JAK1 and TYK2 activity related disease including inflammatory disorders, autoimmune disorders, and cancers other than rheumatoid arthritis. Since there is no precedent in the literature for the treatment of any disease with the above compounds, except for rheumatoid arthritis, how is the skilled physician supposed to know what type of dose regimen of a compound of formula (I) to use for each of the pathologically different diseases?
Determining if any of the claimed compounds will treat any particular disease state would require formulation into a dosage form, and subjecting into clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. This is undue experimentation given the limited guidance and direction provided by Applicants.
Accordingly, the inventions of claims 8 and 9 do not comply with the scope of enablement requirement of 35 U.S.C 112, first paragraph, since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation with no assurance of success.
Allowable Subject Matter
Claims 1-7 and 10 are allowed.
Conclusion
Claims 8 and 9 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RAYNA B RODRIGUEZ whose telephone number is (571)272-7088. The examiner can normally be reached 8am-5:00pm, Monday - Thursday.
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/Rayna Rodriguez/Primary Examiner, Art Unit 1628