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 .
DETAILED ACTION
The office acknowledges Applicants filing of the claims amendments on 9/20/2024. Claims 1-15 have been cancelled and claims 16-34 are new and pending.
Application Priority
This application filed 07/18/2024 is a Continuation of 17293877, filed 05/13/2021, now U.S. 12071431, 17293877 is a National Stage entry of PCT/EP2019/ 081410, International Filing Date: 11/14/2019, claims foreign priority to 18380017.6, filed 11/14/2018.
Information Disclosure Statement
The information disclosure statement(s) (IDS) filed on 3/3/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the Examiner.
Claim Rejections - 35 USC § 112
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 16-34 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated:
"To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir.1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966." Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents" of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of Califorrnia v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP states that for a generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618.
The Guidelines for Examination of Patent Applications Under 35 USC 112, "Written Description" Requirement (Federal Register, Vol. 66, No. 4, pg. ll05, column 3), in accordance with MPEP § 2163, specifically state that for each claim drawn to a genus the written description requirement may be satisfied through sufficient description of a representative number of species by a) actual reduction to practice; b) reduction to drawings or structural chemical formulas; c) disclosure of relevant, identifying characteristics (i.e. structure) by functional characteristics coupled with a known or disclosed correlation between function and structure. The analysis of whether the specification complies with the written description requirement calls for the examiner to compare the scope of the claim with the scope of the description to determine whether applicant has demonstrated possession of the claimed invention (Federal Register, Vol. 66, No. 4, p. ll05, 3rd column, 3rd paragraph). Below is such comparison.
Scope of claims:
The claims are directed to:
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The scope is very broad in regards to the compounds and its use in treating an array of unrelated disorders namely, auto-inflammatory diseases, cardiovascular diseases, osteoarthritis, lung cancer, and gout. Further the patient population is not limited to human subjects.
Scope of disclosure and reduction to practice:
The specification discloses synthesis of select compounds, in vitro binding of p38 MAPK of compound 7, effect of compounds 5 and 7 in the treatment of non-alcoholic steatohepatitis and effect of compound 7 in the treatment of bleomycin-induced idiopathic pulmonary fibrosis (IPF).
The instant specification provide information in regards to IL-1 be involved in inflammation, auto-inflammatory diseases with IL-1 blocking agents. However Applicants have not disclosed the list of conditions to be treated, for e.g. what auto-inflammatory diseases or cardiovascular conditions are being treated, how lung cancer or gout unrelated conditions are being treated with the same compound(s). Based on the substituents of Z1, Z2, Z3, L, R1, R2, R3, X3 and Rx of Formula Ia, hundreds of compounds are being claimed to treat a wide range of conditions.
The following are the teachings from the prior art in relation to the autoinflammatory diseases, cardiovascular conditions and its treatment.
As per Canadian Autoinflammatory network, see below the list of the auto inflammatory diseases (List of Autoinflammatory Diseases -Canadian Autoinflammatory Network | Réseau Auto-inflammatoire Canadien, 2026).
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According to the refernece by An, autoinflammatory disease (AID) is a vast spectrum of disorders characterized by recurrent attacks of sterile inflammation. The pathophysiology of AIDs is complex. Although many are caused by rare mutations in genes that govern innate immunity, others are polygenic, where disease expression is thought to be triggered by environmental factors in genetically predisposed hosts. AIDs range in prevalence from common entities like gout to ultrarare monogenic diseases. Whereas AIDs were initially studied in pediatric populations, it is now apparent that they can present in adulthood and even in the elderly. AIDs can be clinically challenging given their rarity, as well as the heterogeneity in presentation and underlying etiology (See Abstract). In p 849-850, autoinflammatory conditions are listed (f).
Canna teach autoinflammatory diseases are a diverse group of disorders where fever and organ-specific inflammation is caused by an over-active inflammatory response (p 1, para 1). Autoinflammatory diseases are often divided into:
IL-1 mediated diseases, or “IL-1opathies,” which include most periodic fever syndromes such as familial Mediterranean fever, cryopyrin-associated periodic syndrome (CAPS), and hyper IgD syndrome. These diseases often involve a group of inflammatory proteins called the inflammasome, and some show a remarkable response to blocking the cytokine IL-1. Some of the genes involved include: MEFV, NLRP3, MVK, TNFRSF1A, PSTPIP1, IL1RN, and NLRC4.
Interferon-mediated diseases, or “interferonopathies,” which are caused by an over-production of proteins that our bodies usually use to fight viral infections (called interferons). While these patients don’t always have a fever, they can experience devastating brain inflammation, blood cell problems, muscle inflammation, and/or interstitial lung disease. Some of the genes involved include: PSMB8 and other proteasome genes, STING, TREX1, SAMHD1, and IFIH1.
NF-kB mediated diseases are caused by overactivity of one of the body’s most important inflammatory pathways. Patients can have uveitis (swelling in the eye), intestinal inflammation, deep skin rashes, and/or nodules of inflammation called granulomas. Some of the genes involved include: NOD2, TNFAIP3 (A20), OTULIN, and RIPK1.
Many patients don’t fit neatly into one of these categories, but still suffer from autoinflammatory diseases. Some of the genes involved include: ADA2, PLCG2, UBA1, and XIAP (See p 1-p2) (Canna, https://www.chop.edu/conditions-diseases/ autoinflammatory-diseases, 2024).
UPMC disclose systemic autoinflammatory diseases (SAIDs) can cause a broad range of symptoms and other issues that affect your quality of life. This autoinflammatory diseases list includes some of the more commonly known types:
Cryopyrinopathies (Familial cold autoinflammatory syndrome (FCAS), Muckle Wells Syndrome (MWS), and Neonatal onset multisystem inflammatory disease (NOMID). This family of diseases can affect the skin, joints, eyes, and central nervous system. They usually start when you're an infant or in early childhood. Symptoms can include rash (often hive-like), fever, joint pain, meningitis, hearing loss, and inflammation. Symptoms may be triggered when you're exposed to cold temperatures.
Familial Mediterranean fever (FMF). One of the most common genetic SAIDs, it tends to affect people of Mediterranean descent and starts in childhood. FMF causes chronic fevers, chest and belly pain, and skin rashes lasting one to three days.
Haploinsufficiency of A20 (HA20). An autoinflammatory and autoimmune disease where patients typically develop oral and genital ulcers in combination with inflammation of the skin, joints, eyes, liver, kidneys, and/or brain. This is an inherited syndrome; often multiple family members are affected.
Periodic fevers, cervical adenitis, pharyngitis, and aphthous stomatitis (PFAPA). The most common SAID in young children, it causes fevers with swollen lymph nodes, mouth sores, and a sore throat. These may last for days and recur every six weeks. PFAPA may go away on its own after a number of years.
Schnitzler syndrome. This syndrome starts in adults in midlife and often affects men more than women. Symptoms include a hive-like rash and a fever that recurs.
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS). This syndrome causes a high fever that lasts for weeks. Other symptoms include a skin rash, severe stomach, chest, or joint pain, and swelling in or around the eyes.
Systemic Juvenile Idiopathic Arthritis (sJIA) or Adult Onset Still Disease (AOSD). These syndromes typically present with daily episodes of high fevers, joint pain, lymph node swelling, and rash. In some cases, patients may develop cytokine storm syndrome that requires hospitalization.
Vacuoles, E1 ligase, X-linked, Autoinflammatory, Somatic (VEXAS). This disease typically affects men over the age of 50 and combines some features of myelodysplastic syndrome (anemia, low platelet count, and low white blood cell count) with autoinflammation (rashes, inflammation of the nose/ear cartilage, fevers, and lung inflammation) (UPMC, https://www.upmc.com/conditions/s/saids, 2026).
Basaran discusses rare autoinflammatory diseases, see Table 1 for select diseases. For example, A20 Haploinsufficiency (HA20) is an autoinflammatory disease presented with early-onset systemic inflammation and caused by heterozygous loss-of-function mutations in tumor necrosis factor-alpha-induced protein 3 gene (TNFAIP3) (See p 22, col. 2, para 3, 6).
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It is taught that in conclusion, the challenge in the field of autoinflammation continues, where we need further work to understand the pathogenesis and scope of these diseases. Different abnormalities in immune pathways may cause a variety of rare autoinflammatory diseases with uniform or distinct features. Ongoing studies in autoinflammation and innate immunity will highlight a pivotal role in improving diagnostic tools and devel oping specific therapies (See p 23, col. 2, Conclusion) (Turkish Archives of Pediatrics, 2022, 18-25).
In a nutshell, from the prior art it is clear that autoinflammatory disorders fall into a wide spectrum of conditions, genetically different and complex conditions to treat. There is no single drug or treatment for all the autoinflammatory diseases.
As to cardiovascular conditions, it includes conditions that affect the structures or function of your heart. The conditions include but not limited to: coronary artery disease, heart attack, abnormal heart rhythms or arrhythmias, heart failure, heart valve disease, congenital heart disease, cardiomyopathy, pericardial disease, marfan syndrome, vascular disease, atherosclerosis, hypertension, ischemia reperfusion, cardiac hypertrophy, cardiomyopathy, stroke, restenosis etc. Heart disease is also called cardiovascular disease and include coronary artery disease, congenital heart attacks, dilated cardiomyopathy, myocardial infarction, heart failure, hypertrophic cardiomyopathy, mitral valve regurgitation, mitral valve prolapse, aortic stenosis etc. (See https://www.medicalnews today.com/articles/237191#types, 2024). Vascular diseases affect arteries and they include: peripheral artery disease, aneurysm, renal artery disease, atherosclerosis, Raynaud’s disease, peripheral venous disease, ischemic stroke, venous blood clots, blood clotting disorders, Buerger’s disease etc. (See https://www.medicalnews today.com/articles/257484#types, 2023). According to American Heart Association, “Heart and blood vessel disease, also called heart disease, includes numerous problems, many of which are related to atherosclerosis”. The conditions include atherosclerosis, stroke, heart failure, arrhythmia, heart valve problems etc. (https://www.heart.org/en/health-topics/consumer-healthcare/what-is-cardiovascular-disease, AMA, 2024).
Netala review is to cardiovascular disease management. The reference teaches various synthetic drugs including statins, ACE inhibitors, ARBs, β-blockers, calcium channel blockers, antihypertensives, anticoagulants, and antiarrhythmics are fundamental in managing cardiovascular diseases (CVDs). Nonetheless, their side effects such as hepatic dysfunction, renal impairment, and bleeding risks necessitate careful monitoring and personalized treatment strategies (See abstract, Cells 2024, 13, 1471).
In summary, cardiovascular diseases are a group of disorders affecting the heart and blood vessels and are treated differently. Even with the approved drugs like statins have side effects.
Representative number of Examples:
The data provided is limited to synthesis of select compounds, in vitro binding of p38 MAPK of compound 7, effect of compounds 5 and 7 in the treatment of non-alcoholic steatohepatitis, effect of compound 7 in the treatment of bleomycin-induced idiopathic pulmonary fibrosis (IPF).
The structure is the compound of formula Ia and the function is the treatment of auto-inflammatory diseases, cardiovascular diseases, osteoarthritis, lung cancer, gout. Formula Ia encompasses hundreds of compounds with differing core structure based on the substituents, Z, L, Z2 and Z3. The chemical, physical and pharmacological properties of the compounds is influenced based on the structural differences. A correlation between structure and function in achieving the property of wherein administration of the therapeutic composition of formula Ia results in the treatment of a wide array of unrelated diseases.
There is substantial variation within the genus of the compounds and one must describe a sufficient variety of species to reflect the variation within the genus. Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved". See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Due to the unpredictable nature of the effects of the large number of compounds of formula Ia for treating a wide array of autoinflammatory conditions, cardiovascular conditions, lung cancer, gout etc., one of ordinary skill in the art cannot predict from the data provided in the specification for compound 5 and 7 shown to be effective for non-alcoholic steatohepatitis and IPF would be useful in treating the claimed autoinflammatory disease, cardiovascular diseases, lung cancer, osteoarthritis, and gout.
A skilled artisan would not be able to extrapolate from the data provided for fenofibrate to all metabolic regulatory drug compositions or the combination composition of the drugs as in the instant method for treating all the wide range of varying and unrelated conditions.
Applicants have failed to provide guidance or data or evidence as to how the skilled artisan would be able to extrapolate from the disclosure species to make and possibly use of the claimed invention. “A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F 3d at 923; Eli Lilly, 119 at 1568. Instead, the “disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described.”
The specification provides insufficient written description to support the genus encompassed by the claim, Vas-Cath Inc. Mahurkar, 19 USPQ2d 1111, makes clear the "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116).
The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521,222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.").
Thus, the specification fails to provide adequate written description for the use of the composition of formula Ia in treating a wide array of diseases as claimed and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
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 ), 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.
Claim 16 recites a limitation of ‘comprising administering a pharmaceutical composition’. However there is no limitation to whom it is administered. It is suggested that the claim be amended to include the limitation of ‘’a subject’ or ‘a subject in need thereof’.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to UMAMAHESWARI RAMACHANDRAN whose telephone number is (571)272-9926. The examiner can normally be reached M-F- 8:30-5:00 PM (PST).
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/Umamaheswari Ramachandran/Primary Examiner, Art Unit 1627
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