DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Formal Matters
Applicant’s claim amendments and arguments in the reply filed on January 26, 2026 are acknowledged and have been fully considered. Claims 1-17 are pending. Claims 1-17 are under consideration in the instant office action. Applicant’s claim amendments and arguments necessitated a new ground of rejections under 35 USC 103 as set forth below. Accordingly, this office action is made final.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from the previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.
New Rejections-Necessitated by Amendments
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 1-4 and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over BEER et al. (US 2019/0029987, previously cited) and Lone et al. ( Obesity Medicine 18 (2020) 100237, newly cited) in view of Novas et al. (US 2017/0354630) and Vivian et al. (Drugs in Context 2013; 212249, newly cited).
Applicants’ claims
Applicants claim a method for treating diabetic nephropathy in a subject comprising administering to the subject two to three times a day a pharmaceutical composition comprising an active ingredient, wherein the active ingredient comprises 110 to 250 mg of dimethyl fumarate or monomethyl fumarate or a pharmaceutically acceptable salt thereof and….and administering an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) inhibitor to the subject. Applicant also claims other features of their inventions in the dependent claims.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
Beer et al. teach a compound specified by formula (I), in particular dimethylfumarate (trans-1,2-ethylenedicarboxylic acid dimethyl ester) is provided for use in prevention or therapy of gout, acne, pyoderma gangrenosum, Vitiligo, cardiovascular disease, metabolic syndrome, diabetes and/or complications of diabetes. Also provided are a dosage form comprising said compound and a method of treatment comprising administration of said compound to a patient in need thereof (see abstract). According to a first aspect of the invention, a compound specified by formula (I)
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wherein each R1 is independently selected from H and C1-C6 alkyl, is provided for use in prevention or therapy of gout, acne, pyoderma gangrenosum, Vitiligo, cardiovascular disease, metabolic syndrome, diabetes and/or complications of diabetes (paragraph 0011). Within the context of the present specification, the term “complications of diabetes” has its general meaning known in the art. Acute complications of diabetes include diabetic ketoacidosis, nonketonic hyperosmolar coma, hypoglycemia, diabetic coma, respiratory infections and periodontal disease. Possible chronic complications of diabetes include microangiopathy, diabetic cardiomyopathy, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic encephalopathy (including, but not limited to, Alzheimer's type dementia), macrovascular disease, cardiovascular disease, diabetic foot (foot complications due to nerve damage in the feet or poor blood flow to the feet) and skin infections. Complications are far less common and less severe in people who have well-controlled blood sugar levels (paragraph 0015). In certain embodiments, the active ingredient employed in prevention or therapy of gout, acne, pyoderma gangrenosum, Vitiligo, cardiovascular disease, metabolic syndrome, diabetes and/or complications of diabetes, is a mixture of dimethylfumarate and magnesium, calcium and zinc salts of ethylhydrogenfumarate. A commercial preparation marketed as fumaderm comprises, per administration form, 30 mg dimethylfumarate, 67 mg ethylhydrogenfumarate calcium salt, 5 mg ethylhydrogenfumarate magnesium salt and 3 mg zinc salt. Also commercially available is a lozenge comprising 120 mg dimethylfumarate and 95 mg ethylhydrogenfumarate, the latter being administrated as the respective salts of calcium (87 mg), magnesium (5 mg) and zinc (3 mg). These administration forms are similarly considered as possible embodiments of the invention (see paragraph 0020).
Lone et al. teach Diabetic nephropathy (DN) is one of the most common diabetic complication in patients. The present study investigates the role of Dimethyl fumarate (DMF) in prevention of renal fibrosis in streptozotocin induced diabetic nephropathy in Wistar rats (abstract, purpose). 30 adult Wistar rats of any sex weighing 200–240 g were employed in the study. The animals were divided randomly into five groups with six animals each. DN rat model was established by i.p injection of 50 mg/kg Streptozotocin (STZ) in Wistar rats. The diseased animals were treated with three doses of DMF i.e low, medium and high viz. 20, 40 and 80 mg/kg respectively for a period of 3 months. Then, specific test were done to evaluate the activity i.e. assessment of diabetic nephropathy, lipid profile, renal hypertrophy, oxidative stress in kidney and histopathological changes in kidney tissue (see abstract, methods). DMF is an FDA approved drug used in treatment of numerous sclerosis and retains antioxidant activity. The oxidative stress in diabetic models was perceived to inhibit post DMF administration. The study shown remarkably increased anti-diabetic, renoprotective, and hypolipidemic effects of DMF in STZ induced diabetic nephropathy in rats (see abstract, results). STZ induced diabetic rats on treatment with DMF positively decreased the level of glucose in blood, regulated the levels of triglycerides cholesterol with enhancement of urine and serum parameters besides their antioxidant effect on kidney (see abstract, conclusion). Administration of streptozotocin at a single injection of 50 mg/kg, i.p. increased levels of glucose in diabetic group in comparison to normal control group. After four weeks of STZ administration, Dimethyl fumarate was given by oral route at low (20 mg/kg/day), medium (40 mg/kg/day) and high (80 mg/kg/day) doses respectively for 4 continuous weeks. On the end of 8th week, all the parameters were reviewed and analyzed in the diabetic and normal rats undergoing or not receiving drug treatment (see animal treatments section on page 3). The results obtained from the current study concluded that dimethyl fumarate can be an advanced option in preventing diabetic nephropathy. The protective effect shown by dimethyl fumarate such as anti-diabetic, anti-oxidant, hypolipidemic and renoprotective supports its usefulness as a future treatment option for diabetic nephropathy (see conclusion section).
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
BEER et al. and Lone et al. do not specifically teach wherein the pharmaceutical composition is administered two to three times a day. This deficiency is cured by the teachings of Novas et al.
Novas et al. teaches method of treating multiple sclerosis by oral administration of enterically coated tablet comprising dimethyl fumarate (DMF) as an active agent in a preferred dose not greater than 480 mg, e.g. 160-500 mg (abstract; paragraphs 0028-0041, 0217, 0617, 0618, 0686, 0689; claim 1). The enterically coated tablet is a tablet or microtablets (paragraph 0618). The microtablets forms a core of dosage form. The core comprises 43% to 95% DMF and 5% to 57% excipients, by weight of the core. The excipients include disintegrants, lubricants, and filler, which reads on the claimed excipient, such as calcium carbonate (paragraphs 0620-0626, 0630). The DMF is in the form of particles wherein at least 80%, at least 90%, at least 95%, at least 97% or at least 99% have particle size of less than 250 micron, e.g. less than 84% are less than 250 micron (paragraph 0627, table 7). The amount of the lubricant is 0.1-3% based on the weight of the composition without the coating (paragraphs 0645, 0773). The amount of disintegrants is 0.2-20% based on the weight of the composition without the coating (paragraph 0633, 0639, 0640, 0773). The amount of filler is 3.5-15% based on the weight of the composition without the coating (paragraphs 0637, 0638). The microtablets are produced by compression (paragraph 0660). The tablet further comprises seal coating between the enteric coating and the core (paragraphs 0664, 0682, 0683, and table 2). The enteric coating is a methacrylic acid-ethyl acrylate copolymer (paragraph 0667). The seal coat is hydroxypropyl methyl cellulose (paragraph 0668). The reference teaches method of making the tablet comprising the steps of forming the core by mixing DMF with excipients, coating the core with seal coat, and coating the seal coat with enteric coating (paragraphs 0682, 0771-0774; example 1). For example, the compounds and pharmaceutical compositions described herein can be administered to a subject, for example orally, in an amount of from about 0.1 g to about 1 g per day, or for example, in an amount of from about 100 mg to about 800 mg per day. The amount of compounds and pharmaceutical compositions described herein may be administered once a day or in separate administrations of 2, 3, 4, 5 or 6 equal doses per day (paragraphs 0698-0699).
BEER et al., Lone et al., and Novas et al. do not specifically teach administering an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) inhibitor to the subject. This deficiency is cured by the teachings of Vivien et al.
Vivian et al. teach Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors are known to reduce proteinuria and have been the first-line agents in the management of diabetic nephropathy for the past 20 years. This review covers recent studies that compare the benefit of additional blockage of the renin–angiotensin aldosterone system through combination therapy with an ACE inhibitor and ARB, or a direct renin inhibitor (DRI), to monotherapy (see abstract, objective). ACE inhibitors and ARBs are now the mainstay of treatment for diabetic nephropathy. However, combination therapy with an ACE inhibitor and an ARB, or DRI, has not been found to be more effective than monotherapy with an ACE inhibitor or ARB, and may increase the risk of hyperkalemia or acute kidney injury (see abstract, results). Both ACE inhibitors and ARBs remain the first-line agents in attenuating the progression of diabetic nephropathy; however, recent studies suggest that combining an ACE inhibitor with an ARB, or combining a DRI with an ACE inhibitor or ARB, may increase adverse events without clinical benefits to offset them (see abstract, conclusions).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill before the effective filing date of the instant invention to modify the teachings of BEER et al. and Lone et al. by administering the composition two or three times per day because Novas et al. teaches method of treating multiple sclerosis by oral administration of enterically coated tablet comprising dimethyl fumarate (DMF) as an active agent in a preferred dose not greater than 480 mg, e.g. 160-500 mg (abstract; paragraphs 0028-0041, 0217, 0617, 0618, 0686, 0689; claim 1). The enterically coated tablet is a tablet or microtablets (paragraph 0618). The microtablets forms a core of dosage form. The core comprises 43% to 95% DMF and 5% to 57% excipients, by weight of the core. The excipients include disintegrants, lubricants, and filler, which reads on the claimed excipient, such as calcium carbonate (paragraphs 0620-0626, 0630). The DMF is in the form of particles wherein at least 80%, at least 90%, at least 95%, at least 97% or at least 99% have particle size of less than 250 micron, e.g. less than 84% are less than 250 micron (paragraph 0627, table 7). The amount of the lubricant is 0.1-3% based on the weight of the composition without the coating (paragraphs 0645, 0773). The amount of disintegrants is 0.2-20% based on the weight of the composition without the coating (paragraph 0633, 0639, 0640, 0773). The amount of filler is 3.5-15% based on the weight of the composition without the coating (paragraphs 0637, 0638). The microtablets are produced by compression (paragraph 0660). The tablet further comprises seal coating between the enteric coating and the core (paragraphs 0664, 0682, 0683, and table 2). The enteric coating is a methacrylic acid-ethyl acrylate copolymer (paragraph 0667). The seal coat is hydroxypropyl methyl cellulose (paragraph 0668). The reference teaches method of making the tablet comprising the steps of forming the core by mixing DMF with excipients, coating the core with seal coat, and coating the seal coat with enteric coating (paragraphs 0682, 0771-0774; example 1). For example, the compounds and pharmaceutical compositions described herein can be administered to a subject, for example orally, in an amount of from about 0.1 g to about 1 g per day, or for example, in an amount of from about 100 mg to about 800 mg per day. One of ordinary skill in the art would have been motivated to do so because Novas et al. teach that the amount of compounds and pharmaceutical compositions which includes DMF described herein may be administered once a day or in separate administrations of 2, 3, 4, 5 or 6 equal doses per day (paragraphs 0698-0699). One of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of BEER et al., Lone, et al., and Novas et al. because both references teach the use of DMF for the treatment of conditions. In the case where the administration frequencies or dose "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). Furthermore, differences in concentration or particle size or density will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955).
It would have been prima facie obvious to a person of ordinary skill before the effective filing date of the instant invention to modify the teachings of BEER et al., Lone et al., Novas et al., by further administering an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) inhibitor because Vivian et al. teach Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors are known to reduce proteinuria and have been the first-line agents in the management of diabetic nephropathy for the past 20 years. This review covers recent studies that compare the benefit of additional blockage of the renin–angiotensin aldosterone system through combination therapy with an ACE inhibitor and ARB, or a direct renin inhibitor (DRI), to monotherapy (see abstract, objective). ACE inhibitors and ARBs are now the mainstay of treatment for diabetic nephropathy. However, combination therapy with an ACE inhibitor and an ARB, or DRI, has not been found to be more effective than monotherapy with an ACE inhibitor or ARB, and may increase the risk of hyperkalemia or acute kidney injury (see abstract, results). One of ordinary skill in the art would have been motivated to do so because Vivian et al. teach that both ACE inhibitors and ARBs remain the first-line agents in attenuating the progression of diabetic nephropathy; however, recent studies suggest that combining an ACE inhibitor with an ARB, or combining a DRI with an ACE inhibitor or ARB, may increase adverse events without clinical benefits to offset them (see abstract, conclusions). "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). One of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of BEER et al., Lone, et al., Novas et al., and Vivian et al. because all of the references teach BEER et al., Lone, et al., Novas et al. the use of DMF for the treatment of conditions, e,g. diabetic nephropathy (by Beer and Lone et al.) while Vivian et al. teach the use of other agents such as ACE pr ARB inhibitors to treat diabetic nephropathy. With regard to the pharmacokinetic profile or parameters recited in claims 1 and 15, "[I]nherency may supply a missing claim limitation in an obviousness analysis." PAR, 773 F.3d at 1194-1195 ; see also Endo Pharms. Sols., Inc. v. Custopharm Inc., 894 F.3d 1374 , 1381 , 127 U.S.P.Q.2D (BNA) 1409 (Fed. Cir. 2018) ("An inherent characteristic of a formulation can be part of the prior art in an obviousness analysis even if the inherent characteristic was unrecognized or unappreciated by a skilled artisan."). It is long settled that in the context of obviousness, the "mere recitation of a newly discovered function or property, inherently possessed by things in the prior art, does not distinguish a claim drawn to those things from the prior art." In re Oelrich, 666 F.2d 578 , 581 (C.C.P.A. 1981). The Supreme Court explained long ago that "[i]t is not invention to perceive that the product which others had discovered had qualities they failed to detect." Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242 , 249 , 66 S. Ct. 81 , 90 L. Ed. 43 , 1946 Dec. Comm'r Pat. 611 (1945). We too have previously explained that "an obvious formulation cannot become nonobvious simply by administering it to a patient and claiming the resulting serum concentrations," because "[t]o hold otherwise would allow any formulation—no matter how obvious—to become patentable merely by testing and claiming an inherent property." Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344 , 1354 (Fed. Cir. 2012). In In re Kao, we found that the claimed controlled-release oxymorphone formulation was obvious because an inherent pharmacokinetic property of oxymorphone that was present in controlled-release oxymorphone "add[ed] nothing of patentable consequence." In re Huai-Hung Kao, 639 F.3d 1057 , 1070 , 98 U.S.P.Q.2D (BNA) 1799 (Fed. Cir. 2011). In In re Kubin, we found an inherent property obvious, explaining that "[e]ven if no prior art of record explicitly discusses the [limitation], the . . . application itself instructs that [the limitation] is not an additional requirement imposed by the claims on the [claimed protein], but rather a property necessarily present in [the claimed protein]." In re Kubin, 561 F.3d 1351 , 1357 , 90 U.S.P.Q.2D (BNA) 1417 (Fed. Cir. 2009). Our predecessor court similarly concluded that it "is not the law" that "a structure suggested by the prior art, and, hence, potentially in the possession of the public, is patentable . . . because it also possesses an [i]nherent, but hitherto unknown, function which [the patentees] claim to have discovered." In re [*1191] Wiseman, 596 F.2d 1019 , 1023 (C.C.P.A. 1979).
Inherency, however, is a "high standard," that is "carefully circumscribed in the context of obviousness." PAR, 773 F.3d at 1195 . Inherency "may not be established by probabilities or possibilities," and "[t]he mere fact that a certain thing may result from a given set of circumstances is not sufficient." Oelrich, 666 F.2d at 581 (emphasis added) (quoting Hansgirg v. Kemmer, 102 F.2d 212 , 214 , 26 C.C.P.A. 937 , 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939); see also In re Rijckaert, 9 F.3d 1531 , 1533-1534 (Fed. Cir. 1993). Rather, inherency renders a claimed limitation obvious only if the limitation is "necessarily present," or is "the natural result of the combination of elements explicitly disclosed by the prior art." PAR, 773 F.3d at 119511 -96; see also Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362 , 1369 (Fed. Cir. 2012) (relying on inherency where the claims recited "a property that is necessarily present" in the prior art). "If . . . the disclosure is sufficient to show that the natural result flowing from the operation as taught would result in the performance of the questioned function, it seems to be well settled that the disclosure should be regarded as sufficient" to render the function inherent. Oelrich, 666 F.2d at 581 (quoting Hansgirg v. Kemmer, 102 F.2d 212 , 214 , 26 C.C.P.A. 937 , 1939 Dec. Comm'r Pat. 327 (C.C.P.A. 1939)). On appeal, Persion contends that the district court erred in applying the inherency doctrine in its obviousness analysis because Devane does not teach administering its hydrocodone-only formulation to patients with mild or moderate hepatic impairment. Thus, Persion asserts, "'the natural result flowing from the operation as taught' in Devane cannot be the claimed [pharmacokinetic] values for [hepatically impaired] patients." Appellant's Br. 37 (quoting Oelrich, 666 F.2d at 581 ); Reply Br. 19. To the extent Persion contends that inherency can only satisfy a claim limitation when all other limitations are taught in a single reference, that position is contrary to our prior recognition that "inherency may supply a missing claim limitation in an obviousness analysis" where the limitation at issue is "the natural result of the combination of prior art elements." PAR, 773 F.3d at 1194-1195 (emphasis added, internal quotations omitted). Here, the district court specifically found that Devane, together with Jain, the state of the prior art at the time of invention, and the Vicodin and Lortab labels, taught the combination of elements that inherently result in the claimed pharmacokinetic parameters. The district court found that a person of ordinary skill in the art would have been motivated, with reasonable expectation of success, to administer an unadjusted dose of the Devane formulation to hepatically impaired patients. There was also no dispute that the Devane formulation, which was identical to the Zohydro ER formulation described in the patents in suit, necessarily exhibited the claimed parameters under these conditions. Pernix, 323 F. Supp. 3d at 607 , 610 . In this context, the district court did not err by finding that the pharmacokinetic limitations of the asserted claims were inherent and added no patentable weight to the pharmacokinetic claims. Similarly, in the instant case the examiner makes the position that the pharmacokinetic parameters recited in claims 1 and 15 inherency renders the claimed pharmacokinetic parameters obvious since the limitation is "necessarily present," or is "the natural result of the combination of elements explicitly disclosed by the combination teachings of the prior art.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 5-11 and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over BEER et al. (US 2019/0029987, previously cited) and Lone et al. ( Obesity Medicine 18 (2020) 100237, newly cited) in view of Novas et al. (US 2017/0354630, previously cited) and Vivian et al. (Drugs in Context 2013; 212249, newly cited) as applied to claims 1-4 and 15-17 above, and further in view of Karki et al. (WO 2016/081676, previously cited), Bandi et al. (US 2018/0064653, previously cited) and Planells et al. (WO 2015/086467, previously cited).
Applicants’ claims
Applicants claim a method for treating diabetic nephropathy in a subject comprising administering to the subject two to three times a day a pharmaceutical composition comprising an active ingredient, wherein the active ingredient comprises 110 to 250 mg of dimethyl fumarate or monomethyl fumarate or a pharmaceutically acceptable salt thereof and….and administering an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) inhibitor to the subject. Applicant also claims other features of their inventions in the dependent claims.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
The teachings of BEER et al., Lone, et al., Novas et al., and Vivian et al. are described above in detail and are incorporated herein by reference.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
BEER et al., Lone, et al., Novas et al., and Vivian et al. do not specifically teach some of the enteric coated tablet features recited in claims 5-8. While Novas et al. teach seal coating and enteric coating, the reference however does not teach the amount of the seal coating based on the core weight as claimed by claim 5, or the amount of the enteric coating based on the core weight as claimed by claim 5. While Novas teaches and suggests tablet. Novas teaches particle size distribution of at least 80%, at least 90%, at least 95%, at least 97% or at least 99% have particle size of less than 250 micron, e.g. less than 84% are less than 250 micron that embrace the claimed three particle size distribution, however, Novas does not specifically teach the claimed particle size distribution comprising all claimed three distributions as recited in claim 5. These deficiencies are cured by the teachings of Karaki, Bandi, and Planells et al.
Karki teaches pharmaceutical composition for treating multiple sclerosis comprising a core comprising DMF and excipients, functional coating surrounding the core, and an outer enteric coating layer. The amount of DMF in the core is 40-80% and the excipients is 1-50%. The enteric coating forms 5-15% of the total weight of the core and the functional coating forms 2-3% of the total weight of the core. The functional coating is cellulose based and the enteric coating is copolymer of methacrylic acid and methyl methacrylate. The core comprises 120-480 mg DMF. The excipients comprises lubricants, disintegrants, and calcium carbonate. The composition has desirable extended release profile and the pharmacokinetics profiles that show maximized absorption of DMF with reduced the GI side effects (paragraph bridging pages 1 and 2; pages 22-32; claims 284, 285, 290-294, 302, 303, 308, 309, 318, 326, 328, 330).
Bandi teaches pharmaceutical composition comprising DMF for treating multiple sclerosis in the form of tablet having diameter from 5.2-6 mm. The tablet comprises 120-240 mg DMF and the tablet is enterically coated with methacrylic acid ethyl acrylate copolymer. The tablet comprises excipients including disintegrant, lubricant, binder, diluents, etc. (abstract; paragraphs 0008-0024, 0031, 0036; claims).
Planells teaches dosage form comprising DMF that is typically is sieved and/or milled to control its particle size. In a preferred embodiment DMF has a particle size distribution d(10) between 5-20 µm, a d(50) between 30-70 µm, and a d(90) between 80-150 µm (page 8, lines 23-25).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill before the effective filing date of the instant invention to modify the teachings of BEER et al., Lone, et al., Novas et al., and Vivian et al. to provide tablet comprising core comprising DMF, seal coating and enteric coating as taught by Novas, and adjust the weight of the seal coating and the enteric coating relative to the core to 2-3% and 5-15%, respectively, as taught by Karki. One would have been motivated to do so because Karki teaches formulation comprising core comprising DMF, seal coating and enteric coating in such amounts has desirable extended release profile and the pharmacokinetics profiles that show maximized absorption of DMF with reduced the GI side effects. One would reasonably expect formulating a tablet comprising a core comprising DMF, seal coating in amount of 2-3% based on the weight of the core and enteric coating in amount of 5-15% based on the weight of the core, wherein the tablet has desirable extended release profile and pharmacokinetics profiles showing maximized absorption of DMF with reduced GI side effects. Further, one having ordinary skill in the art would have used tablet taught by Bandi to deliver DMF taught by the combination of BEER et al., Lone, et al., Novas et al., and Vivian et al. and Karki because Bandi teaches tablets comprising DMF can be used to deliver 120-240 mg DMF for treatment of for instance multiple sclerosis. Furthermore, one having ordinary skill in the art would have used milled/sieved particles of DMF having particle size distribution of d(10) 20 µm or less, a d(50) 50 µm or less, and a d(90) 1000 µm or less as taught by Planells because Planells teaches such particle size distribution is preferred as typical particle size distribution for DMF. In the case where amounts of ingredients, particle sizes, etc.,"overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). Furthermore, differences in concentration or particle size or density will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955).
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over BEER et al. (US 2019/0029987, previously cited) and Lone et al. ( Obesity Medicine 18 (2020) 100237, newly cited), Novas et al. (US 2017/0354630, previously cited), Vivian et al. (Drugs in Context 2013; 212249, newly cited), Karki et al. (WO 2016/081676, previously cited), Bandi et al. (US 2018/0064653, previously cited) and Planells et al. (WO 2015/086467, previously cited) as applied to claims 1-11, 13, and 15-17 above, and further in view of Raghuvanshi et al. (US 2013/0216619, previously cited).
Applicants’ claims
Applicants claim a method for treating diabetic nephropathy in a subject comprising administering to the subject two to three times a day a pharmaceutical composition comprising an active ingredient, wherein the active ingredient comprises 110 to 250 mg of dimethyl fumarate or monomethyl fumarate or a pharmaceutically acceptable salt thereof and….and administering an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) inhibitor to the subject. Applicant also claims other features of their inventions in the dependent claims.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
The teachings of Beer et al., Lone et al., Novas et al., Vivian et al., Karki, Bandi, and Planells are described above in detail and are incorporated herein by reference.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Beer et al., Lone et al., Novas et al., Vivian et al., Karki, Bandi, and Planells do not specifically teach meglumine as the specific alakalizing agent. It should be noticed that Novas and Karki teach the inclusion of alkalizing agents such as calcium carbonate in overlapping amounts. This deficiency is cured by the teachings of Raghuvanshi et al.
Raghuvanshi teaches alkalinizing agent in a core of a tablet including calcium carbonate and meglumine (paragraph 0045).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill before the effective filing date of the instant invention to modify the teachings of Beer et al., Lone et al., Novas et al., Vivian et al., Karki, Bandi, and Planells to replace calcium carbonate in the core of the tablet taught by the combination of Beer et al., Lone et al., Novas et al., Vivian et al., Karki, Bandi, and Planells with meglumine taught by Raghuvanshi based on suitability and equivalency of both as alkalinizing agent in the core of a tablet. Applicants failed to show unexpected results obtained from using meglumine versus any other alkalinizing agent.
In the case where amounts of ingredients, particle sizes, etc.,"overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). Furthermore, differences in concentration or particle size or density will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955).
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over BEER et al. (US 2019/0029987, previously cited) and Lone et al. ( Obesity Medicine 18 (2020) 100237, newly cited), Novas et al. (US 2017/0354630, previously cited), Vivian et al. (Drugs in Context 2013; 212249, newly cited), Karki et al. (WO 2016/081676, previously cited), Bandi et al. (US 2018/0064653, previously cited) and Planells et al. (WO 2015/086467, previously cited) as applied to claims 1-11, 13, and 15-17 above, and further in view of Manser et al. (US 2016/0228376, previously cited).
Applicants’ claims
Applicants claim a method for treating diabetic nephropathy in a subject comprising administering to the subject two to three times a day a pharmaceutical composition comprising an active ingredient, wherein the active ingredient comprises 110 to 250 mg of dimethyl fumarate or monomethyl fumarate or a pharmaceutically acceptable salt thereof and….and administering an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) inhibitor to the subject. Applicant also claims other features of their inventions in the dependent claims.
Determination of the Scope and Content of the Prior Art
(MPEP 2141.01)
The teachings of Beer et al., Lone et al., Novas et al., Vivian et al., Karki, Bandi, and Planells are described above in detail and are incorporated herein by reference.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP 2141.02)
Beer et al., Lone et al., Novas et al., Vivian et al., Karki, Bandi, and Planells do not specifically teach the thickness of the enteric coating is between 20 µm and 90 µm. This deficiency is cured by the teachings of Manser et al.
Manser et al. teach tablet comprising core comprising active agent and enteric coating for controlled release of the active agent while providing effective protection of the drug in the stomach. The enteric coating layer has thickness between 40 µm and 60 µm (abstract; paragraph 0021).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to a person of ordinary skill before the effective filing date of the instant invention to modify the teachings of Beer et al., Lone et al., Novas et al., Vivian et al., Karki, Bandi, and Planells to adjust the thickness of the enteric coating layer in the tablet taught by the combination of Beer et al., Lone et al., Novas et al., Vivian et al., Karki, Bandi, and Planells to have a thickness of 40-60 µm as taught by Manser because Manser teaches such a thickness of the enteric coating layer provides controlled release of the active agent from the core while protecting of the drug in the stomach. In the case where amounts of ingredients, particle sizes, thickness etc.,"overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). Furthermore, differences in concentration or particle size or density will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235 (CCPA 1955).
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/TIGABU KASSA/Primary Examiner, Art Unit 1619
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