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 .
This is a Final Office Action.
Claims 1, 2, 11, 12, 15, 24, 26, 35, 40, 49, 50, 54, 57, 58 and 60 are pending and under consideration.
Claim Objections
The objection to claims 11 and 12 (corrected from 10) because of the phrase “any one of” is withdrawn based on the amendments.
The objection to claim 49 because of the two commas is withdrawn based on the amendments.
Claims 2, 11, 12, 15, 24, 26, 35, 40, 49, 50, 54 and 58 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 112
The rejection of claims 23 and 24 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the phrase “unsubstituted or substituted C1-C6 deuteroalkyl” or “CD3” in the definition of R8 is withdrawn based on the amendments.
The rejection of claim 49 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the phrase, “substituted heteroalkyl,” is withdrawn based on the amendments.
The rejection of claim 59 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the phrase "TYK-2-mediated disease or condition" is withdrawn based on the amendments.
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 1 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 pre-AIA the applicant regards as the invention.
In claim 1, the phrase, “substituted deuteroalkyl, substituted alkoxy, substituted fluoroalkoxy” is indefinite, see page 6, lines 1-2. The phrases are no longer present in the claims.
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 60 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 rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, intestinal bowel disease, Crohn’s disease and ulcerative colitis, does not reasonably provide enablement for preventing symptoms of rheumatoid arthritis, psoriasis, psoriatic arthritis, atopic dermatitis, intestinal bowel disease, Crohn’s disease and ulcerative colitis; or the treatment or prevention of multiple sclerosis, lupus, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, vitiligo, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, celiac disease, Bechet's disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis. 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.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification 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, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Liebel-Flarsheim Co. v. Medrad, Inc. 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (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. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
The analysis is as follows:
(A) Breadth of claims.
(a) Scope of the compounds. The scope of the compounds embraces millions of compounds of formula (I), with variations at 17 locations on the molecule.
(b) Scope of the diseases covered. The claims are drawn to the treatment of rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal bowel disease, Crohn's disease, ulcerative colitis, celiac disease, Bechet's disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis.
(B) The nature of the invention and predictability in the art: The invention is directed toward the treatment of disease 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).
(C) Direction or Guidance: That provided is very limited. The dosage range information on page 86, line 30, 50 mg to about 500 mg, is generic, the same for the many disorders covered by the specification. Thus, there is no specific direction or guidance regarding a regimen or dosage effective specifically for this or that specific disorder. There is for example no specific discussion of which inflammatory disorders are not actually intended. Only a few inflammatory disorders are named. The dosage information that is provided is generic, that is, it is not linked to any specific disease.
(D) State of the Prior Art: These compounds are tricyclic compounds of formula (I). So far as the examiner is aware, no compound embraced by formula (I) or similar have been used for the treatment of the plethora of diseases embraced by the scope of the instant claims.
(E) Working Examples: The specification provides several in vitro pharmacological assays spanning pages 139-142. There are three assays drawn to 1) HEK-Blue™ IL-23 and IFNa/B Reporter Assays for Profiling TYK2 Pseudokinase (JH2) Inhibition; 2) HTRF-Baseed selectivity Assay; and 3) Example B-3: HEK-Blue™ IL-2 and IFNy Reporter Assays for determining selectivity. However, there are no in vivo pharmacological assays drawn to the treatment of any of the diseases embraced by the instant claims.
(F) Skill of those in the art: The claimed diseases, disorders or conditions embraced by the scope vary widely, with no common or known underlying mode of action.
For example, the skill level for the treatment for type I diabetes is exceptionally low. Type 1 diabetes is an autoimmune disease that results in the irreversible destruction of insulin producing beta cells of the Langerhans islets in the pancreas. Despite the urgent need --- type I diabetes is lethal unless the insulin is somehow replaced --- no pharmaceutical has ever been found effective against this disorder. Diet and exercise cannot reverse or prevent type 1 diabetes, although these are important in regulating the insulin given to the patient. Patients are treated either with insulin replacement therapy, or with transplantation surgery, either islet cell transplantation or, less commonly, pancreas transplantation. These do not treat the disorder per se, but only shield the patient from the lethal consequences. Patients may be given drugs for e.g. nephropathy or poor blood circulation in the feet, but these do not treat the disease itself, only the consequences of the lack of insulin.
The compounds claimed here are TYK2 inhibitors. There are no current TYK2 inhibitors on the market to treat type 1 diabetes, Celiac disease or Bechet's disease.
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Moreover, developing treatments for SLE has proved exceptionally difficult. Development of treatments for SLE has been greatly hindered by several factors:
a) SLE is a complex and poorly understood disease. There has been a failure to explain clearly the etiology and pathogenesis of SLE. The understanding of the genetics of SLE is still rudimentary, and insight into pathogenesis of most of the clinical manifestations is still limited. The effector mechanisms in the pathogenesis of e.g. joint, GI, vasculitic, lung and myocardial manifestations remains speculative insight into their inflammatory pathways, and the mechanisms for CNS disease remains unclear as well. Autoantibodies, complement, and immune complexes all have roles, but how these fit together is unclear.
b) The process of drug development is difficult in SLE because of the considerable inhomogeneity of SLE. There are no specific pathognomonic markers. Instead, there are 11 official criteria, but only four are needed for a diagnosis of SLE, so that 330 diagnostic combinations are theoretically possible. Thus, two patients could each separately satisfy the minimum of 4 with not one overlapping item. As a result, designing experiments is exceptionally difficult, in terms of factors such as parameters recruitment for patients, and evaluating the complex outcome measures. Because SLE is a multisystem disease, there is no one generally accepted scoring system, but instead there are in use different scoring paradigms, including BILAG, SLEDAI, SIS, ECLAM, and SLAM.
c) There is a high level of unpredictability of disease course in a given SLE patient. The disease can wax and wane without any pharmacological intervention, which inevitably increases the background noise that reduces the statistical power of a trial.
d) Murine animal models, while useful in studying many aspects of mechanism, show a progressive, unrelenting course in contrast to the remitting/exacerbating pattern seen in most humans. Moreover, the degree of efficacy seen in the murine models appears to surpass grossly what can be achieved in humans.
e) There is some evidence that patients with SLE display pharmacokinetics and pharmacodynamics much more variable than what has been seen in patient populations with other diagnoses. This makes response to drugs much less predictable.
The skill level for multiple sclerosis is generally considered to be on the low side, with only a handful of drugs --- none of them TYK2 inhibitors --- available, none of them with well-established track records.
These are several of the diseases, disorders or conditions embraced by the scope. Because of the scope of the instant claim language, unrelated diseases will have to be tested. Some of these are already known to be resistant to pharmacological treatment as noted above.
(G) The quantity of experimentation needed: Owing to the factors listed above, especially in points A(b), D and (F), experimentation needed will be extensive.
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.
Applicant traverses by stating, “Applicant submits that TYK2 is a well-validated and understood target for all of the listed indications in claim 61. Specifically, all the diseases recited in claim 61 have the same etiology, namely, each of the claimed diseases are related to the function of the JAK-STAT pathway and specifically to the role of TYK2 in this pathway. Consequently, each of the indications claimed has been studied and shown to be related to TYK2 as mediator of the disease.” Applicant cited 6 references for support. However, the 6 references were not submitted for consideration.
Applicant further states, “Additionally, Applicant kindly notes that an allosteric TYK2 inhibitor (deuravacitinib, sold under the name Sotyktu in the United States) is FDA-approved for treatment of plaque psoriasis, further supporting the use of allosteric TYK2 inhibitors, such as those instantly claimed, with the inflammatory and autoimmune diseases as instantly claimed.”
This is not persuasive. As noted by Applicant, deuravacitinib has been approved for the treatment of plaque psoriasis. Deuravacitinib is not approved for the treatment or prevention of all inflammatory and autoimmune diseases, or any other specific inflammatory or autoimmune disease.
Thus, the rejection is maintained.
Double Patenting
The rejection of claims 1, 2, 9, 11, 12, 15, 18, 24, 26, 35, 40, 47, 49, 50, 54 and 57-61 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 11613548, is withdrawn based on the amendments.
The rejection of claims 1, 2, 9, 11, 12, 15, 18, 24, 26, 35, 40, 47, 49, 50, 54 and 57-61 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12122785, is withdrawn based on the amendments.
The rejection of claims 1, 2, 9, 11, 12, 15, 18, 24, 26, 35, 40, 47, 49, 50, 54 and 57-61 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12084458, is withdrawn based on the amendments.
The rejection of claims 1, 2, 9, 11, 12, 15, 18, 24, 26, 35, 40, 47, 49, 50, 54 and 57-61 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12103937, is withdrawn based on the amendments.
The provisional rejection of claims 1, 2, 9, 11, 12, 15, 18, 24, 26, 35, 40, 47, 49, 50, 54 and 57-61 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 73-87 of copending Application No. 18883438, is withdrawn based on the amendments.
The provisional rejection of claims 1, 2, 9, 11, 12, 15, 18, 24, 26, 35, 40, 47, 49, 50, 54 and 57-61 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 35-41 of copending Application No. 18785870, is withdrawn based on the amendments.
The provisional rejection of claims 1, 2, 9, 11, 12, 15, 18, 24, 26, 35, 40, 47, 49, 50, 54 and 57-61 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 35-41 of copending Application No. 18792201, is withdrawn based on the amendments.
The provisional rejection of claims 1, 2, 9, 11, 12, 15, 18, 24, 26, 35, 40, 47, 49, 50, 54 and 57-61 on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 2, 9, 12, 15, 25, 26, 29, 43, 52, 56, 60-63, 69-71, 78 and 79 of copending Application No. 18546943, is withdrawn based on the amendments.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. 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 SUSANNA MOORE whose telephone number is (571)272-9046. The examiner can normally be reached Monday - Friday, 10:00 am to 7:00 pm.
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/SUSANNA MOORE/Primary Examiner, Art Unit 1624
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