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 .
Non-Final Rejection
The Status of Claims:
Claims 1, 5, 10-11, 13. 17, 20-21, 23, 29,35, 39-40, 47, 51,53, 64-66, and 69 are pending.
Claims 1, 5, 10-11, 13. 17, 20-21, 23, 29,35, 39-40, 47, 51,64-66, and 69 are rejected.
Claim 53 is objected.
DETAILED ACTION
1. Claims 1, 5, 10-11, 13. 17, 20-21, 23, 29,35, 39-40, 47, 51,53, 64-66, and 69, are under consideration in this Office Action.
Priority
2. It is noted that this application is a 371 of PCT/EP2022/067376 06/24/2022 ,which has a priority of 63215054 06/25/2021.
Drawings
3. None.
IDS
4. The IDS filed on 1/10/2025 are reviewed by the examiner.
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 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.
Claim Objections
Claim 53 is objected to because of the following informalities: the boxes surrounding the compounds can be improper. The examiner recommends to remove them from the compounds. 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.
Claims 1, 5, 10-11, 13. 17, 20-21, 23, 29,35, 39-40, 47, 51,64-66, and 69 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 pre-AIA the applicant regards as the invention.
Claims 1, 5, 10-11, 13. 17, 21, 23, 29,35, 39-40, 47, 51,64-66, and 69 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex Parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and /or a common use that flows from the substantial structural feature for the following reasons :
Claim 1 contains the followings:
1 (Original) A compound of Formula (I):
PNG
media_image1.png
122
291
media_image1.png
Greyscale
(I)or a pharmaceutically acceptable salt thereof,
wherein A is a 5-memebered heteroaryl and B is furanyl, piperidinyl or a group having the following structure :
PNG
media_image2.png
149
262
media_image2.png
Greyscale
PNG
media_image3.png
584
786
media_image3.png
Greyscale
The variables of A, B, R2 , R3, RN2, RN3, and RN4 in the Formula (I) are described in the specification in the followings:
A is a 5-memebered heteroaryl (a number of species: 12); B is is furanyl, piperidinyl or a group having the following structure :
PNG
media_image2.png
149
262
media_image2.png
Greyscale
cycloalkyl(a number of species: 15); R2 is -N(H)(5- to 10-membered heteroaryl), -C(6-10)aryl, a 5- to 12-membered bi- or tricyclic ring system, or 5- to 10-membered heteroaryl( a number of species at least: 93); R3, RN2, RN3, and RN4 contain numerous compounds such as alkyl(3-to 8-membered heterocyclyl), 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, -C(1-3)alkyl(3- to 8-membered heterocyclyl), -C(1-3)alkyl(phenyl), 3- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl heteroaryl (a number of species: 78) or aryl (a number of species: 19). Aryl" refers to aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
Cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl.
Heterocyclyl includes dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1 -dioxo-thiomorpholiny.
"Heteroaryl" includes azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b] [1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl).
From the above, it is estimated that each of the A, B, R2 , R3, RN2, RN3, and RN4 rings contains at least from 12 different compounds to 93 different compounds in combination with other variables which contain numerous substituents containing cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups; the claim 1 does read on an extremely high number of possible species due to all the permutations and combinations in terms of mathematically speaking. There is no substantial structural feature (for example a common core) shared by all species; furthermore, there is no indication that the species share a specific common on utility.
In response to this rejection, Applicant should either amend the claims to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims in a fact share a substantial structural feature as well as a common use that flows from the substantial structural feature.
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.
Claim 65 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The claim is not directed to the treatment of the specific diseases, but the method of treating a disease, disorder, or medical condition mediated by NIK activity, comprising administering to a subject in need of such treatment an effective amount of (i) a compound of claim 1.
The specification falls short because data essential for treating numerous a diseases, disorders, or medical conditions mediated by NIK activity by administration of an effective amount of (i) a compound of claim 1.
is not described in the specification. In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. § 112, first paragraph, have been described. They are:
1. the nature of the invention,
2. the state of the prior art,
3. the predictability or lack thereof in the art,
4. the amount of direction or guidance present,
5. the presence or absence of working examples,
6. the breadth of the claims,
7. the quantity of experimentation needed, and
8. the level of the skill in the art.
The Nature of the Invention
The current claim 65 is recited in the followings:
A method of treating a disease, disorder, or medical condition mediated by NIK activity, comprising administering to a subject in need of such treatment an effective amount of a compound of claim 1.
The amount of direction or guidance present
The direction present in the current specification is that the claimed compounds can be used to treat various diseases or conditions mediated by NIK activity. These diseases include inflammatory disorders, autoimmune disorders, cancers, metabolic disorders, and osteoporosis. In some embodiments, the disease, disorder, or medical condition mediated by NIK activity is selected from the group consisting of systemic lupus erythematosus ("SLE"), rheumatoid arthritis ("RA"), Sjogren's syndrome, lupus nephritis, inflammatory bowel disease ("IBD"), ANCA associated vasculitis, myositis, IgG4 associated diseases, bullous pemphigoid, neuromyelitis optica spectrum disorders ("NMOSD"), atopic dermatitis "AD"), hidradenitis supperativa ("HS"), steatosis, non- alcoholic steatohepatitis ("NASH"), primary biliary cirrhosis, leukemias, lymphomas, pancreatic cancer, breast cancer, melanoma, obesity, diabetes, acute kidney injury, IgAN, autosomal dominant polycystic kidney disease ("ADCKD"), membranous nephropathy, osteoporosis, bone resorption (periodontitis), multiple sclerosis ("MS"), immune thrombocytopenic purpura, transplantation, myasthenia gravis, scleroderma, myositis, IgG4 associated diseases, and bullous pemphigoid.
However, the specification is silent and fails to provide guidance as to whether all those diseases require the mechanistic nature of being mediated by NIK activity in the patient with the claimed compounds, i.e. the specification fails to provide a correlation between all those diseases and the activity of NIK in the patient. Also, there is no direction and guidance for how all those diseases would be cured by using the claimed compounds in the claims 1 and 65.
The presence or absence of working examples
There are no examples of treatments of various diseases except for inhibition of auto-phosphorylation of recombinant human NF-kappaB-inducing kinase, and effect of compounds on p-lKKa levels in L363 translocated multiple myeloma cells without any actual data for treating the various diseases mentioned in the above. Thus, the specification fails to provide sufficient working examples as to how those diseases can be treated by using an effective amount of a compound of claim 1 in the patient, i.e. again, there is no direct correlation between the diseases and the claimed compounds directly.
The breadth of the claims
The breadth of the claim is that the claimed compounds can be used to treat all the known diseases benefited by the modulation of NIK activity, without regards as to the side-effect of the claimed compounds on the stated diseases.
The quantity of experimentation needed
The quantity of experimentation needed is undue experimentation. One of skill in the art would need to determine which kinds of those disorders would be benefited by the effect of the claimed compounds and would furthermore then have to determine whether or not the claimed compounds would provide treatment of all the known diseases listed in the above.
The level of the skill in the art
The level of skill in the art is high. However, due to the unpredictability in the pharmaceutical art, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro and in vivo screening to determine which compounds exhibit the desired pharmacological activity and which diseases would benefit from this activity.
Thus, the specification fails to provide sufficient support of the broad use of the claimed compounds for all kinds of diseases-treatment. As a result, necessitating one of skill to perform an exhaustive search for which all the known diseases can be treated by all kinds of the claimed compounds in order to practice the claimed invention.
Genentech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001 (3/13/1997), states that “ a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”.
Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation to test which diseases can be treated by the claimed compound encompassed in the instant claims, with no assurance of success.
Claim 66 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The scope of “autoimmune disorders” is unclear. Consider Autism, Primary sclerosing cholangitis (PSC), Multiple Sclerosis, Idiopathic pulmonary fibrosis, Phacogenic Uveitis, adhesive capsulitis, fibromyalgia, arachnoiditis, Rosacea, Lichen sclerosus, Hidradenitis suppurativa, Multifocal Motor Neuropathy with conduction block (MMN), Polymyalgia Rheumatica, Hailey-Hailey disease (Familial benign chronic pemphigus) and Still's disease. Whether these are or are not autoimmune disorders is not known or in dispute, and indeed determining what is and what is not an autoimmune disorder has proved in numerous cases to be very troublesome. For example, there has been extensive and unresolved scientific debate over whether autism, Multiple Sclerosis and fibromyalgia are or are not autoimmune disorders. Hence, it is not known whether these diseases do or do not fall within the claim, rendering the claim indefinite.
In addition, new candidates for possible autoimmune status arise from time to time. There is some research suggesting that emphysema, and some types of schizophrenia are autoimmune. Just recently there has arisen some evidence from mice studies that OCD might well have an immune component, so OCD may, or may not, be embraced by these claims. The reverse process also occurs. For example, ankylosing spondylitis commonly appears on lists of autoimmune disorders, but recent research is pointing to it not being an autoimmune disorder, but instead an unusual response to infection.
Further complicating matters is that there is a broader and narrower understanding of what constitutes an autoimmune disease, so that what is or is not an autoimmune disease can depend on which concept is employed. A good example is Crohn's disease, which is certainly characterized by immune dysregulation, and commonly is labeled as an autoimmune disease. Yet some consider it not a “true” autoimmune disease. Similarly, whether Chronic GVHD should or should not be considered an autoimmune disease turns to a considerable degree on the definition of an autoimmune disease. Another example is celiac disease, which is a fairly well-understood disorder, normally listed as autoimmune, yet some do not consider it a true autoimmune disorder.
Another difficulty is the area of autoinflammatory diseases, including Familial Mediterranean fever. Although once treated as a type of autoimmune diseases, increasingly, these are not. This turns, at least to some degree, on the question of whether autoimmune disorders should be limited to the adaptive immune system, or also include disorders of the innate immune system. With this becoming accepted, then some disorders such as Schnitzler syndrome, Chronic recurrent multifocal osteomyelitis (CRMO) and Adult onset Still's disease (AOSD) are no longer be considered as autoimmune disorders, and even Behçet’s Disease might well go in this category instead of autoimmune.
The test for indefiniteness is “whether the claim delineates to a skilled artisan the bounds of the invention." SmithKline Beecham Corp. v. Apotex Corp., 74 USPQ2d 1398, 1404. Because of the ambiguities discussed above, once cannot be sure of the actual bounds of this term, what diseases it does and does not embrace, and hence the term is indefinite.
Enablement for the scope of “an inflammatory disorders” generally is not present.
The inflammatory disease includes alopecia areata, erythema multiforme, hidradenitis suppurativa, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita (EBA), acne vulgaris, graft versus host disease (GvHD), chronic obstructive airway disease, obstructive pulmonary disease, allergy, systemic lupus erythematosus, scleroderma, anaphylaxis, diabetic retinosis, retinitis, macular degeneration, uveitis, conjunctivitis, ankylosing spondylitis, osteoporosis, diabetes, diabetic kidney disease, nephritis, Sjogren's syndrome, periodontal disease, alopecia areata, chronic pelvic inflammatory disease, endometriosis, rhinitis, tonsilitis, otitis media, sore throat, cystitis, chronic prostatitis, ocular allergy, keratoconjunctivitis sicca, vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia, polychondritis, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Becker's/Duchenne muscular dystrophy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity.
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.
The specification falls short because data essential for treating many inflammatory diseases by administering to the subject hydroflumethiazide or a pharmaceutically acceptable salt is not described in the specification.
For the compound to be effective against inflammatory diseases generally is contrary to medical science. Inflammation is a process which can take place in virtually any part of the body. There is a vast range of forms that it can take, causes for the problem, and biochemical pathways that mediate the inflammatory reaction. There is no common mechanism by which all, or even most, inflammations arise. Mediators include bradykinin, serotonin, C3a, C5a, histamine, assorted leukotrienes and cytokines, and many, many others. Accordingly, treatments for an inflammatory disorder are normally tailored to the particular type of inflammation present, as there is no, and there can be no “magic bullet” against inflammation generally.
Inflammation is the reaction of vascularized tissue to local injury; it is the name given to the stereotyped ways tissues respond to noxious stimuli. These occur in two fundamentally different types. Acute inflammation is the response to recent or continuing injury. The principal features are dilatation and leaking of vessels, and recruitment of circulating neutrophils. Chronic inflammation or "late-phase inflammation" is a response to prolonged problems, orchestrated by T-helper lymphocytes. It may feature recruitment and activation of T- and B-lymphocytes, macrophages, eosinophils, and/or fibroblasts. The hallmark of chronic inflammation is infiltration of tissue with mononuclear inflammatory cells. Granulomas are seen in certain chronic inflammation situations. They are clusters of macrophages which have stuck tightly together, typically to wall something off. Granulomas can form with foreign bodies such as aspirated food, toxocara, silicone injections, and splinters.
Otitis media is an inflammation of the lining of the middle ear and is commonly caused by Streptococcus pneumoniae and Haemophilus influenzae. Cystitis is an inflammation of the bladder, usually caused by bacteria. Blepharitis is a chronic inflammation of the eyelids that is caused by a staphylococcus. Dacryocystitis is inflammation of the tear sac, and usually occurs after a long-term obstruction of the nasolacrimal duct and is caused by staphylococci or streptococci. Preseptal cellulitis is inflammation of the tissues around the eye, and Orbital cellulitis is an inflammatory process involving the layer of tissue that separates the eye itself from the eyelid. These life-threatening infections usually arise from staphylococcus. Hence, these types of inflammations are treated with antibiotics.
Certain types of anti-inflammatory agents, such as non-steroidal anti-inflammatory medications (Ibuprofen and naproxen) along with muscle relaxants can be used in the non-bacterial cases. The above list is by no means complete, but demonstrates the extraordinary breadth of causes, mechanisms and treatment (or lack thereof) for inflammation. It establishes that it is not reasonable to any agent to be able to treat any inflammatory diseases generally.
Conclusion
Claims 1, 5, 10-11, 13. 17, 20-21, 23, 29,35, 39-40, 47, 51,64-66, and 69 are rejected.
Claim 53 is objected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TAYLOR V OH whose telephone number is (571)272-0689. The examiner can normally be reached 8:00-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at 571-272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/TAYLOR V OH/Primary Examiner, Art Unit 1625 9/05/26
Prosecution Insights