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 . Claims 1-3, 5-7, 9, 11, 13-16, 20-22, 25 and 27-36 are pending in this application.
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 nonobviousness.
Claims 1-3, 5-7, 9, 11 and 13-14 are rejected under 35 U.S.C. 102(a)(1) as anticipated by Li et al. WO 2019047915 A1 or, in the alternative, under 35 U.S.C. 103 as obvious over Bastin et al. Organic Process Research & Development (2000), 4, 427-435. Li et al. at page 26 discloses a pharmaceutical acceptable salt of (S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl-5-chloro-6-fluoro-2-isopropoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide that is the same as applicants (see below).
PNG
media_image1.png
305
877
media_image1.png
Greyscale
Li et al. also discloses the treatment of inflammatory disease or other myriad diseases and pharmaceutical composition that is the same as instant claims 13-14.
PNG
media_image2.png
290
504
media_image2.png
Greyscale
The pharmaceutical acceptable salts are disclosed in paragraphs [0067], [0068] and [0069].
PNG
media_image3.png
266
858
media_image3.png
Greyscale
PNG
media_image4.png
311
860
media_image4.png
Greyscale
PNG
media_image5.png
125
855
media_image5.png
Greyscale
Li et al. teaches a pharmaceutical acceptable salt of (S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl-5-chloro-6-fluoro-2-isopropoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide compound, but fail to name specific pharmaceutical salts, specific amounts of the pharmaceutical salts as disclosed in claims in claims 5-7, 9, and 11.
Bastin et al. Organic Process Research & Development 2000, 4, 427-435
(Salt Selection and Optimization Procedures for Pharmaceutical New Chemical
Entities), discloses how to make different salts that are organic and inorganic salts for a new compound. Since Li reference discloses a pharmaceutical acceptable salt of the claimed compound, a composition, method of use and Bastin et al. teaches to make different salts of a known compound, it is obvious to one skilled in the art to modify the known pharmaceutical acceptable salt of (S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl-5-chloro-6-fluoro-2-isopropoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide compound.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5-7, 9, 11, 13-16, 20-22, 25 and 27-36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,220,506. Although the claims at issue are not identical, they are not patentably distinct from each other because there is overlap between the instant claim and claims 1-22 of U.S. Patent No. 11,220,506. Note that the claimed compound i.e., (S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl-5-chloro-6-fluoro-2-isopropoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide and its pharmaceutical salt is disclosed in claim 21 (column 224) of said patent (see below). Said patent also disclose a method of treatment, process of making and crystalline forms of said compound that is the same as the instant claims.
PNG
media_image6.png
424
380
media_image6.png
Greyscale
The instant claims are drawn to organic and inorganic pharmaceutical salt, crystalline forms of (S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl-5-chloro-6-fluoro-2-isopropoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide compound and a method of treatment. Various organic and inorganic salts are recited in instant claim 3 and a preferred salts of fumarate and D-tartrate are recited in claims 6 and 9 respectively.
The only difference between the patent ‘506 and the instant claims is that said patent does not recite specific salts of (S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl-5-chloro-6-fluoro-2-isopropoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide. Instead, the claim 1 of said patent recites the compound in claim 21 and its pharmaceutical salts in general.
According to Bastin et al. Organic Process Research & Development 2000, 4, 427-435
(Salt Selection and Optimization Procedures for Pharmaceutical New Chemical
Entities), it is obvious to make different salts for a new compound.
PNG
media_image1.png
305
877
media_image1.png
Greyscale
As shown above, the preferred salts (fumarate and tartrate) are listed above at page 428. Thus, the instant claims overlap with claims 1-22 of U.S. Patent No. 11,220,506 and the obviousness double patenting rejection is proper.
Claims 1-3, 5-7, 9, 11, 13-16, 20-22, 25 and 27-36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11,905,294. Although the claims at issue are not identical, they are not patentably distinct from each other because there is overlap between the instant claim and claims 1-23 of U.S. Patent No. 11,905,294. Note that the claimed compound i.e., (S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl-5-chloro-6-fluoro-2-isopropoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide and its pharmaceutical salt is disclosed in claim 23 (see last species in claim 23) of said patent. Said patent teaches a method of use by administering the compound of claim 1 in the instant application.
The instant claims are drawn to organic and inorganic pharmaceutical salt, crystalline forms of (S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl-5-chloro-6-fluoro-2-isopropoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide compound and a method of treatment. Various organic and inorganic salts are recited in instant claim 3 and a preferred salts of fumarate and D-tartrate are recited in claims 6 and 9 respectively.
The only difference between the patent ‘295 and the instant claims is that said patent does not recite specific salts of (S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl-5-chloro-6-fluoro-2-isopropoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide. Instead, the claim 1 of said patent recites the compound in claim 23 and its pharmaceutical salts in general.
According to Bastin et al. Organic Process Research & Development 2000, 4, 427-435
(Salt Selection and Optimization Procedures for Pharmaceutical New Chemical
Entities), it is obvious to make different salts for a new compound.
According to Bastin et al. Organic Process Research & Development 2000, 4, 427-435
(Salt Selection and Optimization Procedures for Pharmaceutical New Chemical
Entities), it is obvious to make different salts for a new compound.
As shown in paragraph 3 above, the preferred salts (fumarate and tartrate) are listed above at page 428. Thus, the instant claims overlap with claims 1-23 of U.S. Patent No. 11,905,294 and the obviousness double patenting rejection is proper.
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 14 and 32 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 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. It is recited a method of treating or preventing a disorder or a disease selected from the group of inflammatory disorder, autoimmune disease and a cancer, but the specification is not enabled for such a scope.
A number of factors are relevant to whether undue experimentation would be required to practice the claimed invention, including “(1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.” In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
(1). Breadth of Claims: Claims 14 and 32 are directed to a method of treating or preventing a disorder or a disease selected from the group of inflammatory disorder, autoimmune disease and a cancer that comprises administering to a subject a therapeutically effective amount of the pharmaceutical composition of claim 13.
The scope of use that applicants intend to claim is very broad. To this day, it is impossible to treat all cancer cells with a single pharmaceutical drug. Please see below for the explanations that cancer cells are broad and different one from the other. Cancer cells can exist in different parts of the body and the nature of these cancer cells differs one from the other. For example, the treatment of bone cancer cannot be the same as the treatment of skin cancer. The drug that inhibits bone cancer cells may require more doses than the cancer cells in skin. The form of delivery for both said cancers (radiation, ointment, tablets, etc.) is not the same. For instance, one has to get deep to the bones to inhibit the cancer cells in the bones, while applying the drug on the surface of the skin can inhibit cancer cells on skin. It is also a fact that some cancer cells need more drugs than the others. It is also true that the compounds could be having antagonistic effect or agonistic effect when administered to the body. Which diseases (cancer cells) are inhibited by the administration of the drug and which are not? Applicants claim that all cancer cells can be treated by single pharmaceutical drugs, thus is not enabled.
It can be shown that cancer cells in general are extraordinarily broad. For a compound or genus to be effective against cancer cells generally is contrary to medical science. Cancer is a disease, 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 cancer. There is no common mechanism by which all, or even most, cancers arise. Accordingly, treatments for a cancer or inhibition of cancer cells are normally tailored to the particular type of cancer cells present, as there is no, and there can be no “magic bullet” against cancer cells generally.
Even the most broadly effective antitumor agents are only effective against a small fraction of the vast number of different cancers known. This is true in part because cancers arise from a wide variety of sources, such as viruses (e.g. EBV, HHV-8, and HTLV-1), exposure to chemicals such as tobacco tars, genetic disorders, ionizing radiation, and a wide variety of failures of the body's cell growth regulatory mechanisms. Different types of cancers affect different organs and have different methods of growth and harm to the body, and different vulnerabilities.
The treatment of “autoimmune diseases” generally would be an unprecedented feat. For a compound or genus to be effective against “autoimmune diseases” generally is contrary to medical science. The “autoimmune diseases” are processes 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 are dozens of such diseases, which have fundamentally different mechanisms and different underlying causes. Known autoimmune disorders include multiple sclerosis, autoimmune uveitis, rheumatoid arthritis, Addison's disease, thyroiditis, atrophic gastritis, myasthenia gravis, idiopathic thrombocytopenic purpura, hemolytic anemia, systemic lupus erythematosus, primary biliary cirrhosis, Wegener's granulomatosis, polyarteritisnodosa, erythema nodosum leprosum, autoimmune uveitis, Guillain-Barré syndrome (GBS), allergic encephalomyelitis, acute necrotizing hemorrhagic encephalopathy, idiopathic bilateral progressive sensorineural hearing loss, aplastic anemia, pure red cell anemia, polychondritis, scleroderma, Stevens-Johnson syndrome, idiopathic sprue, lichen planus, Crohn's disease, Graves ophthalmopathy, sarcoidosis, primary biliary cirrhosis, type I diabetes, autoimmune optic neuritis, uveitis posterior, or interstitial lung fibrosis, alopecia, Sjogren's Syndrome, Goodpasture Syndrome, Myasthenia Gravis, inflammatory bowel disease and many more.
There are both chronic and acute “autoimmune diseases”, most of which lack satisfactory treatment. The intractability of these disorders is clear evidence that the skill level in this art is low relative to the difficulty of the task. Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of practitioners in that art, Genentech vs. Novo Nordisk, 42 USPQ2nd 1001, 1006.
Since no compound has shown clinical efficacy against all autoimmune diseases, thus no in vivo or in vitro assay could be validated for the identification of such a general agent. Applicants' specification logically must lack such assay data.
In fact, there are four basic mechanisms underlying autoimmune disease: 1. Antibody mediated diseases: a specific antibody exists targeted against a particular antigen (protein), which leads to its destruction and signs of the disease. Examples are: auto-immune mediated hemolytic anemia, where the target is on the surface of the red blood cell; myasthenia gravis where the target is the acetylcholine receptor in the neuromuscular junction; hypoadrenocorticism (Addison's) where the targets are the cells of the adrenal gland. 2. Immune-complex-mediated diseases: antibodies are produced against proteins in the body. These combine into large molecules that circulate around the body. In systemic lupus erythematosus (SLE) antibodies are formed against several components in the cell's nucleus (hence the anti-nuclear antibody test (ANA) for SLE). Most notably antibodies are made against the body's double stranded DNA, and form circulating soluble complexes of DNA and antibody, which break down in skin causing an increased sensitivity to ultraviolet light and a variety of signs. As the blood is filtered through the kidneys, the complexes are trapped in the glomeruli and blood vessels, causing the kidney to leak protein - glomerulonephritis. They also cause leakage in other blood vessels, and there may be hemorrhaging, as well as accumulating in synovial fluid and causing signs of arthritis and joint pain. Rheumatoid arthritis results from immune complexes (IgM class antibody called rheumatoid factor) against part of the patient's own immune system (part of its IgG molecules). These form complexes that are deposited in the synovia of the joint spaces causing an inflammatory response, joint swelling, and pain. The collagen and cartilage of the joint breaks down and is eventually replaced by fibrin which fuses the joints - ankylosis. 3. Antibody and T Cell-mediated diseases: T cells are one of two types (the other being B-cells), which mediate immune reactions. Upon exposure to a particular antigen, they become programmed to search for and destroy that particular protein in future. Once a patient has been exposed to an antigen, he will be able to mount a much faster response to it the next time it encounters it. This is the basis of vaccination. Thyroiditis (autoimmune hypothyroidism) seems to be of mixed etiology. Several target antigens have been identified, including thyroglobulin the major hormone made by the thyroid. Auto-antibodies to antigens in the epithelial cells of the thyroid have also been found. The thyroid becomes invaded by large numbers of T and B cells as well as macrophages, which are cells that engulf and destroy other cell types. T cells specifically programmed for thyroglobulin have been identified. 4. Diseases arising from a deficiency in complement: When an antigen and antibody react, they may activate a series of serum enzymes (the complement system) whose end result is either the lysis (breakup) of the antigen molecule or to make it easier for phagocytic cells like the macrophages to destroy it. Patients with deficiencies in enzymes activated early in the complement system develop autoimmune diseases like SLE.
Thus, with such differing mechanisms, it is not logical that a treatment for autoimmune diseases generally can be found.
Enablement for the scope of “inflammation” generally is not present. For a compound or genus to be effective against inflammation 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 inflammation 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.
Cholecystitis is gallbladder inflammation usually caused by a gallstone that cannot pass through the cystic duct. In those cases, it normally cannot be treated by pharmaceuticals but instead the gallbladder is removed. Cholecystitis without the formation of gallstones, called acalculous cholecystitis, is caused by bacteria such as Salmonella, Staphylococcus, Streptococcus (as part of scarlet fever), and leptospirosis, and thus may be treatable by treating the underlying infectious agent. Acute inflammation of the gall bladder can also arise from typhoid; treatment is with antibiotics.
In gout, joint inflammation is caused by the formation of monosodium urate monohydrate (MSU) crystals within the joint space. Acute attacks of gout are treated with colchicine (to inhibit of MSU-induced chemotactic factor release by PMNs) and after the acute phase with allopurinol to control the blood levels of uric acid. Pseudogout, sometimes referred to as calcium pyrophosphate disease (CPPD), is inflammation caused by calcium pyrophosphate (CPP) crystals. It is treated with nonsteroidal anti-inflammatory drugs , corticosteroids and Colchicine.
Sinusitis is the inflammation of the mucosal lining of one or more sinuses. It commonly accompanies upper respiratory viral infections and, in most cases, requires no treatment.
Pharyngitis (tonsillitis) is an inflammatory illness of the mucous membranes and underlying structures of the throat (nasopharynx, uvula, and soft palate). The illness can be caused by bacteria, viruses, mycoplasmas, fungi, and parasites, and uncertain causes, especially Streptococcus pyogenes, adenoviruses, influenza viruses, parainfluenza viruses, Epstein-Barr virus, enteroviruses, and Mycoplasma pneumoniae. Similarly, Osteomyelitis is the inflammation of bones, generally caused by bacteria (most commonly Staphylococcus Aureus). The disease can be caused by fungi or viruses. Dacryoadenitis, an inflammation of the tear gland, can arise from infectious mononucleosis, mumps, gonorrhea, or influenza. Conjunctivitis (pink eye) is inflammation of the conjunctiva and can be caused by many microorganisms, including staphylococci, Haemophilus influenzae, streptococci, gonococci, and viruses such as adenoviruses. Treatment in all of these cases, when possible, is thus to the underlying infectious agent.
Rheumatoid arthritis is an inflammatory bone disease causing destruction of articular cartilage, in which macrophages accumulate in the rheumatoid synovial membrane. Mediators are cytokines, including IL-18 and IL-18, and IFN- .
Pneumonia is an inflammation of the lungs that can be caused by viruses (such as respiratory syncytial, parainfluenza, and influenza), bacteria, fungi, mycoplasmas, rickettsias (especially Q fever), Chlamydia, or parasites. It can also occur as a hypersensitivity, or allergic response, to agents such as mold, humidifiers, and animal excreta, and in such a case would be treated with anti-allergic agents.
Other inflammations in the respiratory system include CF, adult respiratory distress syndrome, asthma and bronchitis.
Myocarditis is an inflammation of the muscular middle layer of the heart (myocardium) Viruses, bacteria, and noninfectious diseases can cause it. Treatment is primarily supportive e.g. drugs may be used to improve the heart's ability to contract and to remove extra fluids from the body. Unless the underlying infectious agent itself is treatable, this inflammation is not itself treated.
Glossitis is inflammation of the tongue. Local causes of glossitis include bacterial or viral infection, mechanical irritation or injury from burns, rough edges of teeth or dental and oral appliances, or other trauma; exposure to irritants (tobacco, alcohol, hot foods, or spices), and sensitization (to e.g. toothpaste, mouthwash, breath fresheners, dyes in candy, plastic in dentures or retainers) anemia and other B vitamin deficiencies, erythema multiform, pemphigus vulgaris, syphilis, and other disorders. It can be inherited. Corticosteroids such as prednisone may be given to reduce the inflammation. Antibiotics, antifungal medications, or other antimicrobials may be prescribed if the cause of glossitis is an infection. Anemia and nutritional deficiencies must be treated, often by dietary changes or other supplements.
Meningitis is an inflammation of the outer covering of the brain and spinal cord. It can be caused by virtually any known infectious agent. Thus, if it is caused by Haemophilus influenzae or Neisseria meningitis, the antibiotic derivative rifampin would be used.
Encephalitis is an inflammation of the brain itself. It is most often caused by a group of arboviruses. Treatment of encephalitis is largely supportive because no specific antiviral agents, except for that which works against herpes simplex virus, are available for therapy.
Hepatitis is an inflammation of the liver, usually caused by viral invasion, notably hepatitis A, B and C, but sometimes Epstein-Barr virus; herpes simplex viruses; measles, mumps, and chicken pox viruses; and cytomegaloviruses. Treatment, when possible, is with antivirals. Inflammation of the liver also take the form of alcoholic hepatitis. Lupoid hepatitis is an autoimmune disorder.
Hemorrhoids is an enlarged or varicose condition of the hemorrhoidal veins and tissues around the anus, either internal or external. Anything which obstructs the free circulation of the blood in the portal system will give rise to hemorrhoids. Constipation, straining at stool, diarrhea, dysentery, rough toilet paper, uncleanliness, pelvic tumors, displacement of the uterus and pregnancy are among the most common causes.
There is a series of inflammatory problems directly connected to neutrophil-endothelial cell adhesion (NECA). These include frostbite injury, bacterial meningitis, acute airway inflammation, allograft rejection, hemorrhagic shock, septic shock, ischemia and reperfusion injuries.
Urethritis is an inflammation of the duct that leads from the bladder to the body's exterior. It is often due to fecal contamination or irritation due to physical or chemical substances (e.g. introduction of foreign bodies into the urethra, bubble bath, or soap) or gonorrhea. Treatment may simply involve the withdrawal of the offending chemical agent, or the administration of antibiotics, when Neisseria gonorrhoeae is involved.
Inflammation can arise from the eruption of teeth in a child (teething).
Inflammation of the nails can arise from chronic paronychia, fungus (especially Candida albicans), trauma, impaired circulation, and dermatitis.
Bright's disease (or glomerulonephritis) is inflammation of the glomeruli and the nephrons, the structures in the kidney that produce urine. It usually results from an infection, such as a streptococcal infection, that occurs somewhere else in the body. There is no real treatment beyond relief of the symptoms.
Thyroiditis is an inflammation of the thyroid gland, and takes three forms. Hashimoto's Thyroiditis (chronic lymphocytic thyroiditis) is the most common type of thyroiditis. It is an autoimmune disorder, and treatment is to start thyroid hormone replacement. For De Quervain's Thyroiditis (subacute or granulomatous thyroiditis), treatment is usually bed rest and aspirin to reduce inflammation. Occasionally cortisone and thyroid hormone may be used. Silent Thyroiditis usually arises following pregnancy. Treatment is usually bed rest with beta blockers.
Regional enteritis (Crohn's disease or ileitis) is an autoimmune disorder which is associated with the presence of Mycobacterium paratuberculosis. It can affect any part of the gastrointestinal tract but most commonly affects the ileum. The inflammation is controlled primarily by regulation of diet, antibiotics if abscesses and fistulas are present, sometimes Prednisone and other corticosteroids, and surgery.
Stomatitis, inflammation of the mouth, and mucositis, inflammation of the mucosa can arise from sources as diverse as Candida albicans, dentures, chemotherapy and radiation therapy to the head, neck or mouth (“Radiation mucositis”). It may be secondary to infection, trauma, systemic diseases or autoimmune mechanisms. These come in many forms, such as aphthous ulcers, Acute Necrotizing Ulcerative Gingivitis i.e. "trench mouth", and Lichen Planus. Herpetiform ulcers treatment has ranged from antibiotics, immunosuppressants and yogurt, to Lactobacillus capsules, tetracycline and systemic steroids. Palliative measures include topical anesthetics, Vitamin E, analgesics, and coating agents. Antiviral agents may be used if viral origin is established.
Pancreatitis is inflammation of the pancreas and can arise from abdominal trauma, or the formation of gallstones that obstruct the common bile duct. It can be associated with excessive ingestion of alcohol; with disorders such as cystic fibrosis or Reye's syndrome; or with scorpion stings. Infectious causes include mycoplasmas, Epstein-Barr viruses, Coxsackie viruses, leptospirosis, hepatitis viruses, mumps, congenital German measles, Ascaris worms, and syphilis. The inflammation per se is generally not treatable. Treatment is usually supportive and consists of the management of pain and intravenous feeding.
Neuroretinitis is inflammation of the retina and optic nerve of the eye (“optic neuritis”). It is often idiopathic. It frequently arises secondary to some kind of infection, such as Hepatitis B, HSV, EBV, influenza A, mumps, Coxsackie B, TB, salmonella, Lyme disease, syphilis, leptospirosis, Histoplasmosis, Toxoplasmosis, toxocara, Sarcoidosis and cat-scratch disease. Treatment is thus to the underlying cause. For example, Diffuse unilateral subacute neuroretinitis (DUSN) arises from nematodes deep in the retina or in the subretinal space. Anthelminthic treatment is then used. When the origin is Toxoplasmosis, then anti-Toxoplasma medications such as Pyrimethamine.
Other eye inflammations include scleritis and episcleritis, inflammation of tissues on the sclera; choroiditis, inflammation of the middle coat (choroid) of the eyeball, and uveitis, which is inflammation of the parts of the eyes that make up the iris.
Gastritis is inflammation to the stomach lining. Atrophic gastritis is characterized by the loss of the stomach cells that are responsible for manufacturing acid, pepsin, and intrinsic factor. This condition occurs in older people or those suffering from Helicobacter pylori. Erosive (hemorrhagic) gastritis occurs when shallow ulcers or sores develop on the upper layer of the stomach lining, usually because of the excessive ingestion of a stomach irritant such as aspirin or alcohol.
There can also be mentioned appendicitis, which can occur when a hard piece of stool blocks the opening of the appendix, causing swelling and inflammation.
The great majority of skin problems involve some type of inflammation, such as response to physical injury (e.g. sunburn, ticks, abrasion, or a bee string), acute allergic contact dermatitis (such as poison ivy), and infections (such as boils and cold sores). Ingrowing hairs, or pili incarnati, can cause acute pustular reactions. Cancerous lesions of the skin frequently show some degree of inflammatory response. Acne’s inflammation is caused by leakage of sebum and keratin debris outside the distended pilosebaceous duct. The bacillus Propionibacterium acnes, which populates the lesions, may also contribute indirectly to this inflammation by metabolizing the sebum to produce irritant fatty acids. Inflammation in skin problems is usually the result of the release of chemical mediators in the skin, notably histamine, peptides (kinins) and fatty acids (prostaglandins and leukotrienes), which are formed enzymatically in response to e.g. injury. Medications designed to counteract inflammation in the skin may or may not antagonize the effects of the particular type of mediator involved, if that is known. The inflammation can take many different forms, including redness, (from dilation of blood vessels); heat, (from increased blood flow); swelling (from leakage of fluid from the small blood vessels); whealing reactions (hives, nettle rash, urticaria) in which vascular changes predominate, and pain or itching. Blisters (from enzymes released from inflammatory cells, resident cells of the skin, or blood plasma components) can cause the breakdown of proteins responsible for the structural integrity of the skin, leading to serious inflammatory disorders such as pemphigus. In addition, the affected skin may feel indurated (hardened) because of the deposition of the coagulation protein fibrin and the infiltration by inflammatory blood cells (lymphocytes, histiocytes, and polymorphonuclear leukocytes).
Prostatitis, inflammation of the prostate, comes in several different forms, including those of bacterial origins, and those which are not, including chronic abacterial prostatitis and asymptomatic inflammatory prostatitis. 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 inflammation generally.
PDE IV is predominant in inflammatory cells and, specifically, modulates leucocyte activation. PDE IV inhibitors would be expected to produce bronchodilation and have a certain anti-inflammatory effect , in particular, blocking mediator synthesis (and release) in mast cells, and basophils.
(2). Direction of Guidance: There is no guidance in the specification for a method of treating or preventing inflammatory disorder, autoimmune disease or cancer in general.
(3). State of Prior Art: There is no evidence of record that the pharmaceutical salt of (S)-3-(1-(8-amino-1-methylimidazo[1,5-a]pyrazin-3-yl)ethyl-5-chloro-6-fluoro-2-isopropoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide compound or structurally similar to the compound are in use for the treatment of cancer, inflammation or autoimmune disorders in general.
(4). Working Examples: The working examples at pages 29 -30 provide a pharmacokinetic data, but it is impossible to corelate this data to the treatment or prevention of cancer, autoimmune disease or inflammatory disorders in general.
(5). Nature of the Invention and Predictability: The invention is directed to a method of treating or preventing a disorder or a disease selected from the group of inflammatory disorder, autoimmune disease and a cancer in general. 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).
(6). The Quantity of Experimentation Necessary: Immense, because so many cancerous cells are covered; see part (1).
(7). The Relative Skill of Those in the Art: The relative skill is extremely very low. To this day, there is no magic bullet that can treating or preventing inflammatory disorder, autoimmune disease or cancer in general.
In regard to the prevention, to this day the only available means is the treatment of patients with specific cancer, specific inflammatory disease or specific autoimmune disease and not the prevention of inflammatory disorder, autoimmune disease or cancer in general in the first place.
To overcome this rejection, the examiner recommends that applicants delete “preventing” and also recite specific cancers, inflammatory diseases or autoimmune diseases to overcome this rejection.
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 1-2, 13-16, 20, 29-31 and 34 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention:
a. Claim 1 and claims dependent thereon are rejected because the phrase “inorganic salt(s) or organic salt(s)” is indefinite. What is covered and what is not? How can one tell if a given organic or inorganic salt is not embraced by the claim? It is recommended that applicants recite specific salts as it was done in claim 3.
b. Claim 20 and claims dependent thereon are rejected because the phrase “organic acids or inorganic acids” is indefinite. What is covered and what is not? How can one tell if a given organic or inorganic acid is not embraced by the claim? It is recommended that applicants recite specific organic or inorganic acids as it was done in claim 21.
c. Regarding claims 29 and 34, the term "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Note that applicants deleted said term from other claims.
Information Disclosure Statement
12. Applicant’s Information Disclosure Statement, filed on 11/22/2023 has been acknowledged. Please refer to Applicant’s copies of the 1449 submitted herewith.
Conclusion
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kahsay Habte Ph.D. whose telephone number is (571)272-0667. The examiner can normally be reached on 8:30 - 5:00 PM.
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, JEFFREY MURRAY can be reached on 571-272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see https://ppair-my.uspto.gov/pair/PrivatePair. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Kahsay Habte/
Primary Examiner, Art Unit 1624