DETAILED ACTION
Status of Claims
Receipt is acknowledged of the Applicants’ Amendments and Remarks, filed January 14, 2025, which have been entered on the record.
Claims 2-3, 6-7, 12-13, 15, 18, 23, 25, 27, 29, 31, and 33 are canceled.
Claims 4, 8, 10, 16, 19, 21, 24, 28, 30, 34, and 36 are amended.
Claims 1, 4, 5, 8-11, 14, 16-17, 19-22, 24, 26, 28, 30, 32, and 34-36 are pending and under consideration.
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 .
Information Disclosure Statement
Two information disclosure statements (IDS) submitted on May 2, 2025, and January 14, 2025 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
Abstract Objections
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because the abstract is less than 50 words. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
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.
Claim 36 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.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to: (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. See MPEP § 2164.01 (a).
Upon consideration of the factors discussed below, the examiner concludes that one skilled in the art would be unable to practice the invention as disclosed without being burdened with undue experimentation based on the information provided by the applicant.
A discussion of these factors in relation to the pending claims follows.
The breadth of the claims and nature of invention
Claim 36 is directed towards a method of preventing or treating a CaMKII associated disease or condition, comprising administering a therapeutically effective amount of a crystalline form of claim 1.
On page 26, paragraph [0114], Applicant discloses a broad range of heterogenous conditions, and diseases associated with CaMKII.
Specifically, Applicant discloses that “is expected to be useful for the prophylaxis or treatment of, for example, cardiac diseases (cardiac hypertrophy, acute heart failure and chronic heart failure including congestive heart failure, cardiomyopathy, angina, myocarditis, atrial/ventricular arrhythmia, tachycardia, myocardial infarction, etc.), myocardial ischemia, venous insufficiency, post-myocardial infarction transition to heart failure, hypertension, cor pulmonale, arteriosclerosis including atherosclerosis (aneurysm, coronary arterial sclerosis, cerebral arterial sclerosis, peripheral arterial sclerosis, etc.), vascular thickening, vascular thickening/occlusion and organ damages after intervention (percutaneous coronary angioplasty, stent placement, coronary angioscopy, intravascular ultrasound, coronary thrombolytic therapy, etc.), vascular reocclusion/restenosis, after bypass surgery, cardiac hypofunction after artificial heart lung surgery, respiratory diseases (cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombus/pulmonary embolism, etc.), bone disorders (nonmetabolic bone disorders such as bone fracture, refracture, bone malformation/spondylosis deformans, osteosarcoma, myeloma, dysostosis and scoliosis, bone defect, osteoporosis, osteomalacia, rickets, osteitis fibrosis, renal osteodystrophy, Paget's disease of bone, myelitis with rigidity, chronic rheumatoid arthritis, gonarthrosis and articular tissue destruction in similar disorders thereof, etc.), inflammatory diseases (diabetic complication such as retinopathy, nephropathy, nerve damage, macroangiopathy etc.; arthritis such as chronic rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, periostitis etc.; inflammation after surgery/trauma; reduction of swelling; pharyngitis; cystitis; pneumonia; atopic dermatitis; inflammatory enteric diseases such as Crohn's disease, ulcerative colitis etc.; meningitis; inflammatory eye diseases; inflammatory pulmonary diseases such as pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis etc., and the like), allergic diseases (allergic rhinitis, conjunctivitis, gastrointestinal allergy, pollen allergy, anaphylaxis, etc.), drug dependence, neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, AIDS encephalopathy, etc.), central nervous system damage (disorders such as cerebral hemorrhage and cerebral infarction and aftereffects and complications thereof, head injury, spinal damage, cerebral edema, sensory dysfunction, sensory abnormality, autonomic dysfunction, abnormal autonomic function, multiple sclerosis etc.), dementia, disturbed memory, disturbed consciousness, amnesia, anxiety symptoms, nervous symptoms, unpleasant condition, mental disorders (depression, epilepsy, alcohol dependency, etc.), ischemic peripheral circulatory disorder, deep-vein thrombosis, occlusive peripheral circulatory disorder, arteriosclerosis obliterans (ASO), occlusive thromboangiitis, diabetes (type 1 diabetes, type 2 diabetes, pregnancy diabetes etc.), diabetic complications (nerve damage, nephropathy, retinopathy, cataract, macroangiopathy, osteopenia, diabetic hyperosmolar diabetic coma, infectious diseases, diabetic gangrene, xerostomia, deterioration in hearing, cerebrovascular damage, peripheral circulatory disorder, etc.), urinary incontinence, metabolic/nutritional disorders (obesity, hyperlipidemia, hypercholesterolemia, diabetes, impaired glucose tolerance, hyperuricemia, hyperkalemia, hypernatremia etc.), metabolic syndrome, vesceral obesity syndrome, male or female sexual dysfunction and the like, and for the prophylaxis or treatment of dysgeusia, smell disturbance, abnormal circadian rhythm of blood pressure, cerebrovascular damage (asymptomatic cerebrovascular damage, transient cerebral ischemia attack, stroke, cerebrovascular dementia, hypertensive encephalopathy, cerebral infarction, etc.), cerebral edema, cerebral circulatory disturbance, recurrence and aftereffects of cerebrovascular damages (neurological symptoms, mental symptoms, subjective symptoms, impairment of activities of daily living, etc.), kidney diseases (nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, diabetic nephropathy, nephrotic syndrome, hypertensive nephrosclerosis, complications of dialysis, organ damage including nephropathy by irradiation, etc.), erythrocytosis/hypertension/organ damage/vascular thickening after transplantation rejection after transplantation, ocular disorders (glaucoma, ocular hypertension, etc.), thrombosis, multiple organ failure, endothelial dysfunction, hypertensive tinnitus, other circulatory diseases (ischemic cerebral circulatory disturbance, Raynaud's disease, Buerger's disease, etc.), chronic occlusive pulmonary diseases, interstitial pneumonia, carinii pneumonia, connective tissue disorders (e.g., systemic erythematosus, scleroderma, polyarteritis, etc.), liver disorders (hepatitis and cirrhosis including chronic types, etc.), portal hypertension, digestive disorders (gastritis, gastric ulcer, gastric cancer, disorder after gastric surgery, poor digestion, esophageal ulcer, pancreatitis, colon polyp, cholelithiasis, hemorrhoidal problem, esophageal and gastric variceal rupture, etc.), hematological/hematopoietic disorders (erythrocytosis, vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation syndrome, multiple myelosis, etc.), solid tumor, tumors (malignant melanoma, malignant lymphoma, digestive organs (e.g., stomach, intestine, etc.) cancers, etc.), cancers and cachexia associated therewith, cancer metastases, endocrine disorders (Addison's disease, Cushing's syndrome, pheochromocytoma, primary aldosteronism, etc.), Creutzfeldt-Jakob disease, urological/male genital diseases (cystitis, prostatic enlargement, prostate cancer, sexually transmitted diseases, etc.), gynecological disorders (menopausal disorders, pregnancy toxemia, endometriosis, uterine fibroid, ovarian diseases, mammary gland diseases, sexually transmitted diseases, etc.), diseases caused by environmental/occupational factor (e.g., radiation damage, damage from ultraviolet/infrared/laser beam, altitude sickness etc.), infectious diseases (viral infectious diseases of, for example, cytomegalovirus, influenza virus and herpesvirus, rickettsial infectious diseases, bacterial infectious diseases, etc.), toxemia (septicemia, septic shock, endotoxic shock, gram-negative septicemia, toxin shock syndrome, etc.), ear nose throat diseases (Ménière's disease, tinnitus, dysgeusia, vertigo, balance disorder, deglutition disorder etc.), cutaneous diseases (keloid, hemangioma, psoriasis, etc.), dialysis hypotension, myasthenia gravis, systemic diseases such as chronic fatigue syndrome, and the like, particularly cardiac diseases (particularly catecholaminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure, fatal arrhythmia) and the like, in a subject in need thereof.”
All of the diseases and conditions aforementioned are broad classes of diseases with high heterogeneity in terms of patient population, response to treatment, etiology, etc.
By example only, Applicant claims to treat the broad class of infectious diseases which includes viral infectious disease such as herpesvirus and solid tumor, tumors (malignant melanoma, malignant lymphoma, digestive organs (e.g., stomach, intestine, etc.) cancers, etc.), cancers.
By example only, it is well-known in the art of virology that viruses are not homogenous entities and are incredibly diverse with respect to genetic makeup, structure, replication mechanism, host interactions, and other factors.
Jones et al. explains that “Viral heterogeneity poses a difficult challenge for medicine. Adequate medical interventions are still lacking for many viral infections, particularly the ones discussed in this Review (Jones, Jennifer E., Valerie Le Sage, and Seema S. Lakdawala. "Viral and host heterogeneity and their effects on the viral life cycle." Nature Reviews Microbiology 19, no. 4 (2021): 272-282).”
Jones further explains “Current technologies make it easier than ever before to screen thousands of compounds for efficacy against viral infection and rapidly identify potential new therapeutic candidates. Nevertheless, these results should be interpreted with caution. A given virus may exhibit extraordinary diversity in genomic content and particle morphology, so candidate therapeutics must be pan-protective against a heterogeneous viral population.”
Woolhouse also teaches that “The lines of evidence described earlier combine to suggest the following tentative model of the emergence process for novel human viruses. First, humans are constantly exposed to a huge diversity of viruses, though those of other mammals (and perhaps birds) are of greatest importance. Moreover, these viruses are very genetically diverse and new genotypes, strains and species evolve rapidly (over periods of years or decades).”
Woolhouse also teaches that “There are 219 virus species that are known to be able to infect humans. The first of these to be discovered was yellow fever virus in 1901, and three to four new species are still being found every year. Extrapolation of the discovery curve suggests that there is still a substantial pool of undiscovered human virus species, although an apparent slow-down in the rate of discovery of species from different families may indicate bounds to the potential range of diversity. More than two-thirds of human viruses can also infect non-human hosts, mainly mammals, and sometimes birds. Many specialist human viruses also have mammalian or avian origins. Indeed, a substantial proportion of mammalian viruses may be capable of crossing the species barrier into humans, although only around half of these are capable of being transmitted by humans and around half again of transmitting well enough to cause major outbreaks. A few possible predictors of species jumps can be identified, including the use of phylogenetically conserved cell receptors. It seems almost inevitable that new human viruses will continue to emerge, mainly from other mammals and birds, for the foreseeable future (Woolhouse, M., Scott, F., Hudson, Z., Howey, R. and Chase-Topping, M., 2012. Human viruses: discovery and emergence. Philosophical Transactions of the Royal Society B: Biological Sciences, 367(1604), pp.2864-2871).”
As another example, cancer, including tumors, is a broad class of heterogenous diseases for which there exists no general treatment or prevention. Hanahan explains that “there are more than 100 distinct types of cancer, and subtypes of tumors can be found within specific organs” (Hanahan, Douglas, and Robert A. Weinberg. "The Hallmarks of Cancer." Cell 100, no. 1 (2000): 57-70).
Hanahan further comments that “Cancer is daunting in the breadth and scope of its diversity, spanning genetics, cell and tissue biology, pathology, and response to therapy (Hanahan, D., 2022. Hallmarks of cancer: new dimensions. Cancer discovery, 12(1), pp.31-46).”
Hanahan further teaches that “We noted as an ancillary proposition that tumors are more than insular masses of proliferating cancer cells. Instead, they are complex tissues composed of multiple distinct cell types that participate in heterotypic interactions with one another…Cancer cells are the foundation of the disease; they initiate tumors and drive tumor progression forward, carrying the oncogenic and tumor suppressor mutations that define cancer as a genetic disease. Traditionally, the cancer cells within tumors have been portrayed as reasonably homogeneous cell populations until relatively late in the course of tumor progression, when hyperproliferation combined with increased genetic instability spawn distinct clonal subpopulations. Reflecting such clonal heterogeneity, many human tumors are histopathologically diverse, containing regions demarcated by various degrees of differentiation, proliferation, vascularity, inflammation, and/or invasiveness (Hanahan, D. and Weinberg, R.A., 2011. Hallmarks of cancer: the next generation. cell, 144(5), pp.646-674).”
Consequently, Hanahan teaches the diversity, heterogeneity and complexity of cancer as a disease of which there remains no general treatment, despite years of research and improved understanding.
The Examiner emphasizes Applicant’s listing of diseases is broad and inclusive of a wide-range of heterogenous diseases and conditions varying in etiology, pathology, and treatment options.
Page 6, paragraph [0040] Applicant defines treating as "Treatment" or "treat" or "treating" as used herein refers to an approach for obtaining beneficial or desired results. For purposes of the present disclosure, beneficial or desired results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a disease or condition. In some embodiments, "treatment" or "treating" includes one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) relieving the disease or condition, e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.”
Consequently, the scope of invention is broad with respect to the aim of “treating” and is inclusive of prevention and curing.
On page 6, paragraph [0043] Applicant defines subject as: "Subject" refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In some embodiments, the subject is a human. In some embodiments, the subject is a patient.”
Therefore, it is reasonable to conclude the claims are broad with respect to subject which includes all animals, including mammals and humans.
Consequently, it is reasonable to conclude that the claims are broad with respect to subject, disease, and aim of “treating,” which includes curing.
The state of the prior art
The state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains. The relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed. See MPEP § 2164.05(b). See Pac. Biosciences of Cal., Inc. v. Oxford Nanopore Techs., Inc., 996 F.3d 1342, 1352, 2021 USPQ2d 519 (Fed. Cir. 2021).
The state of the prior art provides evidence for the degree of predictability in the art and is related to the amount of direction or guidance needed in the specification as filed to meet the enablement requirement. The state of the prior art is also related to the need for working examples in the specification. See MPEP § 2164.05 (a).
To the best knowledge of the examiner, there is no compound and/or general treatment known to treat the wide range of diseases and/or disorders claimed including cancer, cardiac diseases, and infectious diseases.
Pertaining CaMKII inhibitors, Tian teaches several challenges in targeting CaMKII such as “(1)Multiple activation modes through PTMs…. (2)Numerous isoforms and variants with similar structures…. An ideal CaMKII inhibitor should be able to distinguish among its various isoforms. Due to the high structural similarity, designing isoform-specific CaMKII inhibitors remains a significant challenge… ( 3)Broad distributions across diverse tissues. CaMKII is widely distributed in various organs and tissues (Fig. 2). Therefore, when addressing drug absorption issues, it is essential not only to ensure effective accumulation in the target organ (e.g., a tumor-bearing organ) but also to avoid unintended distribution to non-target organs, such as the heart or nervous system, where off-target effects could interfere with their physiological functions (Nicoll and Schulman, 2023). Similarly, drugs acting on the cardiovascular system should also consider their potential off-target effects on the nervous system… (4) Dual role in physiology and disease. Elevated CaMKII activity or expression is strongly linked to diseases, yet CaMKII also plays crucial roles in normal functions (Fig. 2) (Anderson, 2021, Beckendorf et al., 2018). An even greater challenge lies in the fact that, even if a drug is successfully restricted to a diseased organ, CaMKII within that organ may still be involved in both pathological and physiological processes, necessitating precise discrimination between its harmful and essential activities within the same tissue environment. Therefore, CaMKII inhibitors should possess the capacity to differentiate between the physiological and pathological effects of CaMKII, allowing for selective inhibition of its pathological effects while preserving its physiological functions (Tian, Xinmiao, Xianghui Wang, Sichong Chen, Xuefei Sun, Dongxue Shao, Kuo Zhang, Qinghua Gao, and Liying Hao. "Ca2+/Calmodulin-dependent protein kinase II (CaMKII)-targeted drug discovery: Challenges and strategies." Ageing Research Reviews (2025): 102886).”
Tian also teaches that “The dual physiological and pathological roles of CaMKII underscore the critical need to distinguish between its normal and aberrant activity, which remains a major challenge in therapeutic development.”
Applicant has not demonstrated that the crystalline compound as claimed has been able to overcome such challenges; moreover, Applicant has not provided any working examples demonstrating methods of treatment towards any of the diseases and conditions as claimed.
Therefore, it is reasonable to conclude that the current state of the art is highly unpredictable, indicating that more details, working examples and guidance would be required to practice the invention as disclosed for all types of cancer, infectious diseases and other disorders and conditions as claimed across all subjects as claimed in instant invention.
The level of one of ordinary skill
The person of ordinary skill in the art is a hypothetical person who is presumed to have known the relevant art at the relevant time. Factors that may be considered in determining the level of ordinary skill in the art may include: (A) "type of problems encountered in the art;" (B) "prior art solutions to those problems;" (C) "rapidity with which innovations are made;" (D) "sophistication of the technology; and" (E) "educational level of active workers in the field. In a given case, every factor may not be present, and one or more factors may predominate." In re GPAC, 57 F.3d 1573, 1579, 35 USPQ2d 1116, 1121 (Fed. Cir. 1995); Custom Accessories, Inc. v. Jeffrey-Allan Indus., Inc., 807 F.2d 955, 962, 1 USPQ2d 1196, 1201 (Fed. Cir. 1986); Environmental Designs, Ltd. V. Union Oil Co., 713 F.2d 693, 696, 218 USPQ 865, 868 (Fed. Cir. 1983). See MPEP § 2141.03 (I)
The invention described pertains to the biomedical and pharmaceutical arts. One of ordinary skill would be a person with considerable training in medicine, veterinary medicine, pharmacology, oncology, medicinal chemistry, biochemistry or a related technical discipline.
The level of predictability in the art
The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The "amount of guidance or direction" refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling.
The scope of the required enablement varies inversely with the degree of predictability involved, but even in unpredictable arts, a disclosure of every operable species is not required. A single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements. In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971). However, in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. See MPEP § 2164.03.
Consequently, technologies involving physiological activity as opposed to mechanical or electrical inventions are generally regarded as being unpredictable sciences.
As aforementioned, cancer, infectious diseases and many of the other diseases claimed are highly heterogenous classes of diseases and disorders additionally known to be highly unpredictable. There is no single compound known to treat or cure such a broad range of diseases and conditions as claimed in instant invention.
Additionally, Applicant has not provided any working examples.
In this context, based on assessing the fields of study, the predictability in the art is very low.
Consequently, the applicant would need to provide more details, working examples and guidance in order for the claimed invention to be enabling based on the scope and nature of the claimed invention.
The amount of direction provided by the inventor
As aforementioned, the amount of direction provided depends on the prior art and predictability of in the art. Based on the scope of protection sought by the applicant and the discussion aforementioned, the inventor has failed to provide sufficient direction for one ordinarily skilled in the art to practice the disclosed invention as claimed.
The existence of working examples
Applicant has provided no working examples demonstrating that the crystalline form as claimed is effective in treating any of the diseases or conditions claimed.
On this basis and the prior discussion, the working examples are both not commensurate with the scope of protection sought and are not enabling. One ordinarily skilled in the art would unable to simply translate the evidence provided by the applicant into methods encompassing the broad scope of subjects, diseases, compounds and aim of treatment as claimed without undue experimentation.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
As aforementioned, the quantity of experimentation depends on the prior art, the predictability of the art, and the direction provided by the inventor, which are factors that were already discussed.
In order for one ordinarily skilled in the art to practice the invention as disclosed, some attributes one would require, but are not limited to:
Actual working examples such as in vitro & in vivo studies (i.e.: actual preclinical data or clinical data) encompassing the diverse class of subjects listed (i.e.: humans, mammals, and other animals) and broad range of cancer, infectious diseases and other diseases and conditions claimed.
Support demonstrating curative effects (i.e.: remission) as claimed.
Additional details on development of a treatment regime including how to determine effective dosage, timing, monitoring plan and administration method for the diverse class of subjects, diseases and disease progression.
Based on the preponderance of evidence and rationale put forth, the examiner concludes that one ordinarily skilled in the art would require undue experimentation in order to practice invention based on the details provided and scope of invention defined in Claim 36.
Consequently, claim 36 is rejected for lacking enablement.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being clearly anticipated by Matsunaga et al (WO 2022/ 067082 A1).
Matsunaga discloses the identical compound of Formula (I) as a crystalline form.
Specifically, on page 205, Example 321, Matsunaga discloses the identical compound (4-fluoro-2-[5-(6-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl]benzonitrile) as a residue that is further purified and “crystallized from EtOAc/IPE to give the titled compound as an off-white solid.”
Therefore, claim 1 is rejected as being anticipated by Matsunaga.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
Claims 1, 4, 5, 8-11, 14, 16-17, 19-22, 24, 26, 28, 30, 32, and 34-35 are rejected under 35 U.S.C. 103 as being unpatentable over Matsunaga et al (USPN 11,795,172 B2) in view of Bastin et al. (Bastin, Richard J., Michael J. Bowker, and Bryan J. Slater. "Salt selection and optimisation procedures for pharmaceutical new chemical entities." Organic Process Research & Development 4, no. 5 (2000): 427-435), Newman (Newman, A., 2013. Specialized solid form screening techniques. Organic Process Research & Development, 17(3), pp.457-471) and Thorson et al. (Thorson, M.R., Goyal, S., Schudel, B.R., Zukoski, C.F., Zhang, G.G., Gong, Y. and Kenis, P.J., 2011. A microfluidic platform for pharmaceutical salt screening. Lab on a Chip, 11(22), pp.3829-3837).
Regarding Claims 1, 4, 5, 8-11, 14, 16-17, 19-22, 24, 26, 28, 30, 32, and 34, Matsunaga discloses Example 321, columns 138 to 139, lines 60-67, and lines 1-10, the identical compound (4-fluoro-2-[5-(6-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl]benzonitrile) as a residue that is further purified and “crystallized from EtOAc/IPE to give the titled compound as an off-white solid,” as per claim 1.
Matsunaga does not explicitly disclose crystalline Forms A, B or C and their XRPD characterization as per claims 4-5, and 8-11.
Matsunaga also does not explicitly disclose a co-crystal such as an L-tartaric acid, fumaric acid, hydrochloride, methanesulfonate and phosphoric acid co-crystal and their characterizations as per claims 4, 16-17, 19-22, 24, 26, 28, 30, and 32.
Matsunaga also does not explicitly disclose preparing Form C as per claim 35.
Matsunaga does teach that “Compound (I) can be obtained in the crystal form. Either single crystalline form or crystalline mixture can be encompassed in compound (I).
Compound (I) can be a pharmaceutically acceptable co-crystal or a co-crystal salt. The co-crystal or co-crystal salt as used herein means a crystalline material composed of two or more unique solids at room temperature, each of which has distinctive physical characteristics such as structure, melting point, and heats of fusion, hygroscopicity, solubility, and stability. A co-crystal or a co-crystal salt can be produced according to co-crystallization method known per se (column 89-90, lines 63-67 and lines 1-6 respectively).”
Matsunaga also teaches that “When compound (I) is a salt, examples of the salt include metal salts, ammonium salts, salts with organic base, salts with inorganic acid, salts with organic acid, and salts with basic or acidic amino acid. Preferable examples of the metal salt include alkali metal salts such as sodium salts, potassium salts and the like; alkali earth metal salts such as calcium salts, magnesium salts, barium salts and the like; and aluminum salts. Preferable examples of the salt with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Preferable examples of the salts with basic amino acid include salts with arginine, lysine, ornithine and the like. Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like. Among them, a pharmaceutically acceptable salt is preferable. For example, when a compound has an acidic functional group, examples of the salt include inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt etc.) and the like, ammonium salt etc., and when a compound has a basic functional group, examples of the salt include salts with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and salts with organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like (column 89, lines 19-55).”
Consequently, Matsunaga teaches crystalline forms of formula (I) and preferable examples using the co-crystals as claimed in instant invention.
Matsunaga also teaches that compound of formula (I) can be used as a pharmaceutical comopostion: “Compound (I) or a prodrug thereof (to be abbreviated as the compound of the present invention) is superior in vivo kinetics (e.g., plasma drug half-life, intracerebral transferability, metabolic stability), shows low toxicity (e.g., more superior as a medicament in terms of liver/hepatotoxicity, acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, cytotoxicity, drug interaction, carcinogenicity etc.; especially liver/hepatotoxicity). The compound of the present invention is directly used as a medicament or a pharmaceutical composition mixed with a pharmaceutically acceptable carrier or the like to be orally or parenterally administered to mammals (e.g., humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep and goats) in safety (column 104, lines 43-56).”
Newman teaches “Polymorph screens focus on finding new forms of an API and can include unsolvated, solvated, hydrated, and even amorphous materials. Salt, cocrystal, and amorphous dispersion screens use additional materials, such as counterions, cocrystal formers, and polymers, respectively. For all solid forms, small screens in early development may lead to medium size screens for phase II or III trials and a more comprehensive screen near launch. It should be noted that, once a new salt or cocrystal is targeted for development, a polymorph screen should be performed on that material to determine the possible forms, the thermodynamically stable form, and how this new form best fits within the development plan.”
Consequently, Newman teaches that screening for polymorphs is an important part of routine optimization in developing pharmaceuticals.
Newman also teaches common solvents used for a stable form screen as used in instant invention such as water, methyl ethyl ketone, and acetone (Table 1).
Bastin teaches the workflow and process for salt selection and optimization procedures for pharmaceutical new chemical entities (entire article). Specifically, Bastin teaches categories and examples of different salt classes for performing salt screening including many screened in instant invention (Table 1, page 428).
Bastin teaches microplate techniques for screening salts, scale-up, and HPLC as a tool to test sample purity, noting specifically that “Knowledge of the approximate purity is important at this stage as the presence of high levels of some impurities can often hinder crystallization or alter the polymorphic form obtained (page 428).”
Bastin also teaches various motivations to prepare salts including solubility, taste masking, and physical stability (column 1, paragraph 2, page 429).
Bastin also teaches common tests employed for evaluating salts during the optimization process, including XRD, DSC, and HPLC to test for chiral purity (Table 3 and Table 8).
Thorson teaches that “A key challenge to identify salts of parent compounds (PCs) is screening an extensive number of salt formers (SFs) under a variety of crystallization conditions with limited material. Extensive screens are traditionally conducted at various conditions to identify salts with suitable properties for formulation development because many parameters influence crystallization of salts, including SF identity, PC to SF ratios, solvents employed, pH, and temperature. To carry out high-throughput screens, automated robotic systems have been developed, which improve efficiency and reduce turnaround time… This study presents a microfluidic approach that addresses these challenges by enabling extensive salt screenings with reduced sample requirement and much improved control over the crystallization processes.”
Thorson also teaches “The microfluidic platform reported here can also find its application in salt screening using evaporation and/or antisolvent modes. Other high throughput crystallization applications include the screening for crystal habit, polymorphs or co-crystals covering wide ranges of conditions while using minimal amounts of material. Furthermore, modifications to the microfluidic chips, specifically the mixing zone and chamber geometries, would change the rate of supersaturation, thereby influencing crystallization events. In summary, with simple modifications, this platform could be used to study the nucleation, polymorphism and crystal habit of drugs and other compounds.”
Consequently, Thorson teaches that salt and polymorph screening of pharmaceutical compounds can be achieved with improved efficiency and requiring minimal material via routine optimization using a microfluidic platform and/or automated robotic systems.
Consequently, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Matsunaga, Bastin, Newman and Thorson towards accessing crystalline forms A-C of instant invention and co-crystal salts because Matsunaga discloses the identical compound and teaches that the compound can be crystallized, converted into pharmaceutically acceptable salts and used in pharmaceutical compositions, Bastin teaches salt selection and optimization processes and the benefits of salt formation without altering chemical structures, Newman teaches common solvents used in a stable form screen including those used in instant invention and that such a screen is routine optimization in pharmaceutical sciences. Thorson additionally teaches that polymorph screening can be achieved with improved efficiency as a routine optimization using automation.
A person of ordinary skill in the art of process chemistry and/or pharmaceutical sciences would have been motivated to purify Matsunaga’s compound and to perform Newman and Bastin’s stable form screen and salt screening processes to arrive at the claimed invention as part of pharmaceutical scale-up and manufacturing process optimization. Such a process would arrive at the method of preparation as disclosed in claim 35. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success in arriving at the claiming invention as a highly predictable result with a reasonable expectation of success.
It would have been also prima facie obvious to perform standard characterization of Crystal forms A-C and the co-crystals such as XRD as part of crystallization optimization process as is well-known in the art as standard analytical techniques to characterize API in scale-up, recrystallization and process optimization in the pharmaceutical sciences.
Finally, it would have been further prima facie obvious to develop pharmaceutical compositions as a highly predictable result with a reasonable expectation of success as Matsunaga teaches pharmaceutical compositions using the identical compounds and its pharmaceutically acceptable salts and such experimentation would be part of routine optimization in the drug development process in preparing pharmaceutical compositions for methods of treatment.
Consequently, an ordinary-skilled artisan would arrive at the claimed inventions as a predictable result with a reasonable expectation of success.
Conclusion
Claims 1, 4, 5, 8-11, 14, 16-17, 19-22, 24, 26, 28, 30, 32, and 34-36 are under consideration and are rejected. No claims allowed.
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/C.L.L./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
