Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
The amendment to the claims filed after non-final office action on February 19, 2026 is acknowledged. Claim 28 was amended, claims 39-41 were newly added, claims 1-27, 29, 31-37 were canceled and claims 28, 30, 38-41 are pending in the instant application. The restriction was deemed proper and made final in a previous office action.
Claims 28, 30, 38-41 are examined on the merits of this office action.
Maintained Objections
Claim 38 is objected to for the following informality: the limitation “sulfonyll urea” in line 6 should be replaced with -sulfonylurea-.
Maintained/Revised Rejections
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 28, 30 and 38-41 are/remain rejected under 35 U.S.C. 103 as being unpatentable over Chen (US20140148382 A1, cited previously) in view of Drucker (Cell Metabolism 24, July 12, 2016, cited previously).
Regarding claim 28, Chen teaches a method of administering a glycine tripeptide, including Gly Gly Leu (diapin) to a patient that has prediabetes, diabetes, obesity or metabolic syndrome (see claims 1, 7-12). Patients that have prediabetes, metabolic syndrome and or obesity are patients in need of preventing/treating atherosclerosis and do not necessarily have diabetes. Regarding claim 30, Chen additionally teaches treating wherein the patient has chronic kidney disease (see claim 19) and coronary artery disease (see paragraph 0070). Chen additionally teaches treating the diabetes associated complication of atherosclerosis (see paragraph 0070). Chen specifically teaches that diapin stimulated GLP-1 secretion, insulin secretion and lowers blood glucose levels (see Figures 7-10). Chen teaches “The amount of the composition administered is therapeutically effective to achieve at least one of the following: reducing blood glucose levels, stimulating insulin secretion, stimulating GLP-1 secretion, reducing insulin resistance, and improving glycemic control” (see paragraph 0066). Regarding “relative to baseline”, in view of the specifications consistent use of “baseline” to denote measurements taken after one week of diet and before treatment of administration, a person of ordinary skill would understand “relative to baseline” to mean relative to subjects pre-treatment level.
Regarding claim 38, Chen teaches administering an additional therapeutic agent including a DPP-4 inhibitor (see paragraph 0075) and other diabetes drugs for treatment of diabetes, prediabetes and/or metabolic syndrome.
Although Chen does not explicitly teach treatment of atherosclerosis in an example, it recognizes that atherosclerosis as a complication of prediabetes, diabetes and metabolic syndrome and therefore implies therapeutic benefit in managing associated vascular pathologies in patients that are non-diabetic.
Drucker teaches that “Both native GLP-1 and GLP-1R agonists reduce cardiac and vascular inflammation through direct and indirect mechanisms (Figure 1). Multiple studies have demonstrated that GLP-1R agonists, including native GLP-1, exenatide (synthetic exendin-4), and liraglutide, often administered at doses that do not produce weight loss, attenuated the development of atherosclerosis in genetically sensitized murine models. These peptides reduced vascular monocyte adhesion and/or macrophage accumulation within blood vessels of several strains of normoglycemic or dysglycemic mice at high risk for the development of experimental atherosclerosis and cardiac dysfunction.” (see page 17, left column, last paragraph into right column, see also Figure 2, GLP-1 actions in the vessels, increase plaque stability, reduce platelet aggregation). Thus, Drucker attributes the anti-atherosclerotic effect to the action of GLP-1 on immune cell trafficking and inflammation.
It would have been obvious before the effective filing date of the claimed invention to treat patients with atherosclerosis with the compositions of Chen (and inclusive to those without diabetes such as metabolic syndrome and prediabetes). One of ordinary skill in the art would have been motivated to do so given that improving glucose utilization, insulin sensitivity and increasing GLP-1 secretion would be beneficial in treating patients with atherosclerosis independent of diabetes as taught by Drucker. There is a reasonable expectation of success given Chen teaches treating patients with atherosclerosis as a complication with prediabetes/metabolic syndrome. Furthermore, a person of ordinary skill in the art would have been motivated to combine the teachings of Chen and Drucker and administer the instant peptides of Chen for the treatment of atherosclerosis, based on their known ability to stimulate GLP-1 secretion and the teaching in Drucker that GLP-1 activity reduces atherosclerotic plaque formation via modulation of immune responses. One would have a further reasonable expectation of success in using the peptides to treating atherosclerosis, even in a non-diabetic patient, given the mechanistic rationale provided in Drucker and the known effects of GLP-1 on vasculature and inflammation.
Chen does not teach specifically use the peptides in combination with GLP-1 or a synthetic variant thereof (the elected species). However, Chen does teach “Glucagon-like peptide-1 (GLP-1) is an incretin hormone. Incretin hormones are secreted by intestinal cells in response to nutrient ingestion. The primary physiological function of GLP-1 appears to be related to glycemic control. GLP-1 stimulates insulin release, inhibits glucagon secretion, reduces gastric emptying and augments satiety. Administration of GLP-1 to patients has been reported to restore blood glucose regulation via endogenous insulin secretion. GLP-1 administration has also been reported to reduce energy intake through its actions of delaying gastric emptying and increasing satiety, therefore it may induce weight loss.
MPEP states “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) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious). But see In re Geiger, 815 F.2d 686, 2 USPQ2d 1276 (Fed. Cir. 1987) (“Based upon the prior art and the fact that each of the three components of the composition used in the claimed method is conventionally employed in the art for treating cooling water systems, the board held that it would have been prima facie obvious, within the meaning of 35 U.S.C. 103, to employ these components in combination for their known functions and to optimize the amount of each additive....Appellant argues... hindsight reconstruction or at best,... obvious to try’.... We agree with appellant.”). One of ordinary skilled in the art would have been motivated to combine the two each known (GLP-1 and variants thereof with GGL, which also stimulates GLP1 naturally) to be useful for the same purpose (treating atherosclerosis in patients without diabetes such as prediabetics and metabolic syndrome), with a reasonable expectation that at least here will be an additive effect.
It would have been obvious before the effective filing date of the claimed invention to administer the peptide treatment of Chen in combination with an additional GLP-1 agent because GLP-1 receptor agonists are well known for improving glycemic control, reducing bodyweight, improving lipid parameters, and providing cardiovascular benefits in subjects with metabolic diseases and also atherosclerosis. One of ordinary skill in the art would have been motivated to combine Chen’s therapy with a GLP-1 agent to enhance overall therapeutic effectiveness.
Regarding the limitations of “reduces atherosclerotic plaque burden in the aorta, wherein the administering reduces plasma LDL cholesterol levels, wherein the administering reduces hepatic triglyceride content and hepatic total cholesterol levels in the subject”, Chen in view of Drucker teach the same method of the instant claims including administering the same peptide Gly-Gly-Leu at a therapeutically effective amount to patients with atherosclerosis and thus, these effects would necessarily occurring as result of practicing the method of Chen in view of Drucker and due to the inherent properties of Gly-Gly-Leu as taught by Chen and Drucker (see MPEP 2112).
Furthermore, since the peptides of Chen Elevate GLP-1 and Drucker establishes that GLP agonism in non-diabetic subjects has anti-atherogenic effects and anti-lipid affects (liver fat reduction), it would have been reasonably expected that administration of the peptides in Chen would result in the same downstream effects.
More specifically, with respect to claim 28, the limitations of administrating increases hepatic expression of fatty acid oxidation genes comprising PPARa and CPT1a, reduces atherosclerotic plaque burden in the aorta, reduces plasma LDL cholesterol, and reduces hepatic triglyceride and total cholesterol merely described biological consequences of administering the known peptide to treat the same metabolic and cardiovascular conditions including atherosclerosis. Chen teaches administration of the identical tripeptides for treatment of metabolic disorders associated with dyslipidemia and cardiovascular risk, while Drucker teaches that GLP-1 mediated signaling improves atherosclerosis, inflammation and lipid metabolism. Because Applicant relies on administration of the same tripeptide compounds to achieve these effects, such downstream metabolic and anti-atherogenic results would inherently accompany the prior art method, even if not previously quantified or expressly recognized (see MPEP 2112).
With respect to claims 39–41, the recited increases in ABCG5/ABCG8, reduction of MCP-1, and suppression of NF-kB signaling are likewise result-oriented effects of the method of Chen and Drucker.
These limitations merely recite additional molecular markers or mechanistic correlates of improved cholesterol transport and reduced inflammation that naturally accompany treatment with the same known tripeptide compounds. Because Chen in view of Drucker teaches administration of the identical peptides for the same indications (treatment of atherosclerosis) and because Applicant attributes these effects to administration of the same peptides, such recited biomarker changes are inherent effects of the known treatment or at minimum expected biological consequences thereof, even if not previously recognized in the art (see MPEP 2112).
Regarding claim 30, treatment of an atherosclerosis complication such as coronary artery disease in addition to atherosclerosis, it would have been obvious before the effective filing of the claimed invention to administer the claimed composition to a subject having atherosclerosis and a complication thereof, such as coronary artery disease. One of ordinary skill in the art would have been motivated to do so because coronary artery disease is a recognized atherosclerotic condition involving plaque accumulation in the coronary arteries. There would have been a reasonable expectation of success given that Chen teaches treatment of coronary artery disease and related metabolic cardiovascular disorders using the disclosed peptide compositions. Because coronary artery disease is a known atherosclerotic condition, one of ordinary skill in the art would have reasonably expected a therapy effective for atherosclerosis to produce similar beneficial effects in subjects with coronary artery disease.
Response to Applicant’s Arguments
The Applicant respectfully disagrees. However, for purposes of expediting prosecution, Claim 28 is now amended to additionally recite, " wherein the administering increases hepatic expression of fatty acid oxidation genes comprising PPARα and CPT1a relative to baseline..." In addition, new Claims 39-41 are added which are directed to, wherein the administering increases expression of ABCG5 and ABCG8, wherein the administering reduces plasma MCP-1, wherein the administering suppresses NF-kB signaling." The rejection under 35 U.S.C. §103 over Chen in view of Drucker rests on the premise that the claimed reductions in plaque burden and hepatic lipid parameters would have been expected consequences of GLP-1 mediated biology. Amended Claim 28, however, now requires that administration of Gly-Gly-Leu or Gly-Gly-dLeu increases hepatic 4 expression of PPARα and CPT1a, key regulators of fatty acid ß-oxidation. This limitation shifts the claim from generalized lipid outcomes to defined hepatic transcriptional modulation. A person of skill in the art reviewing Chen would necessarily note that it is directed primarily to glycemic control and metabolic disease contexts in diabetic models. It does not disclose plaque regression in non-diabetic subjects, nor does it teach induction of hepatic fatty acid oxidation genes such as PPARα and CPT1a. The Examiner therefore relied on Drucker remedy the deficiencies of Chen and supply the expectation that GLP-1 biology would produce the claimed hepatic and vascular effects. The very portions of Drucker cited by the Examiner, however, defeat that premise. As shown in the attached excerpts, Drucker explains that although GLP-1 receptor agonists reduce liver fat and hepatic inflammation in some studies, hepatocytes "do not express the canonical GLP-1R," and reductions in liver fat and hepatic lipoprotein synthesis are "likely indirect," mediated in part by changes in circulating insulin and glucagon levels, neural inputs, weight loss, enhanced insulin sensitivity, or altered substrate delivery. Specifically, the Examiner is directed pages 7-8 of Drucker which directly supports the distinction that it teaches hepatic lipid improvements are indirect and not due to direct GLP-1 receptor signaling in hepatocytes (see, yellow highlights). Drucker further acknowledges that results from preclinical and clinical studies of GLP-1 agonists are "sometimes contradictory," reflecting differences in species, experimental methodology, pharmacokinetics, and duration of administration, as recited on page 2.
With respect to atherosclerosis specifically, Drucker states that experiments examining GLP- 1R signaling in plaque development and vascular inflammation yield inconsistent results depending on experimental conditions. Respectfully, the Applicant asserts that these statements from Drucker are dispositive. Inherency requires that a claimed feature necessarily and inevitably flow from the prior art disclosure. Where the art itself characterizes hepatic lipid effects as indirect and expressly recognizes inconsistent and model-dependent outcomes in atherosclerosis studies, there can be no finding that induction of hepatic PPARα and CPT1a expression is an inevitable or predictable result of administering a GLP-1-stimulating peptide. At most, Drucker suggests that GLP-1 signaling may indirectly influence metabolic parameters under certain conditions; it does not establish that GLP-1 elevation necessarily induces the specific hepatic fatty acid oxidation program recited in the amended claim. By contrast, the present specification expressly demonstrates coordinated upregulation of hepatic fatty acid oxidation regulators PPARα and CPT1a (see, e.g., III [0102], [0136]-[0137], and experimental confirmation at I [0320] and I [0398]), together with associated improvements in hepatic triglyceride and cholesterol content and reduction in atherosclerotic plaque burden (see Il [0321]). The specification further links these effects to restoration of fatty acid β-oxidation pathways rather than generalized systemic metabolic changes (II [0398]-[0400]). This represents a defined hepatic transcriptional mechanism centered on FAO induction, not merely a downstream systemic consequence of GLP-1 signaling. As neither Chen nor Drucker teaches or suggests that GLP-1 biology necessarily induces hepatic PPARα and CPT1a expression in a non-diabetic subject with atherosclerosis, and because Drucker expressly characterizes hepatic lipid effects as indirect and atherosclerosis outcomes as inconsistent and model-dependent, the combination of Chen and Drucker does not render amended Claim 28 obvious.
Applicants arguments have been fully considered but not found persuasive. The rejection does not rely solely on express disclosure of each newly recited biomarker in the prior art. Rather, the rejection is based on the administration of the same previously known tripeptides, Gly-Gly-Leu and Gly-Gly-dLeu, taught by Chen for treating diabetes, prediabetes, metabolic syndrome and associated complications including atherosclerosis, to the same patient population for the same therapeutic purpose, namely treatment of metabolic and cardiovascular disease states including atherosclerosis. Where the prior art teaches the same compound used in the same manner, newly discovered properties, mechanisms of action, or biological results flowing from that known use do not render the claim patentable. See MPEP § 2112.
With respect to amended claim 28, the added limitations that administration increases hepatic expression of PPARα and CPT1a, reduces plaque burden, lowers LDL cholesterol, and reduces hepatic triglyceride and total cholesterol merely recite biological effects resulting from administration of the same known tripeptide compounds. Chen teaches the identical peptides for treatment of metabolic disorders and improvement of glucose/lipid homeostasis, and further teaches that the peptides promote glucose utilization, improve insulin sensitivity and increase GLP-1 secretion. Chen additionally teaches treatment of associated complications including atherosclerosis. Drucker teaches that GLP-1 biology improves vascular inflammation, atherosclerosis, and hepatic lipid parameters and was cited as further evidence and motivation that enhancement of GLP-1 signaling would have made use of Chen’s known peptides for treatment of atherosclerosis obvious. Accordingly, the recited effects are inherent properties of administering the same peptides to the same patients population for the same therapeutic purpose, or at minimum excepted downstream biological consequences of practicing the method of Chen as further supported by Drucker. See MPEP § 2112(I).
Applicant’s argument that Drucker describes certain hepatic effects as “indirect” is not persuasive. Whether the known beneficial effects occur through direct receptor signaling or indirect systemic pathways does not distinguish the claimed method. Patentability does not turn on whether the precise biological mechanism is direct or indirect wherein the beneficial therapeutic effects of GLP-1 signaling were already known or suggested by the prior art.
Applicant’s reliance on statements that some GLP-1 studies produced inconsistent outcomes also is unpersuasive. Obviousness requires only a reasonable expectation of success, not absolute predictability or universal consistency across all models. See MPEP § 2143.02 MPEP states “Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")).” Drucker nonetheless affirmatively teaches anti-atherogenic, anti-inflammatory, and lipid-improving effects of GLP-1 signaling sufficient to motivate use of Chen’s GLP-1-stimulating peptides for the same purpose.
With respect to claims 39–41, the recited increases in ABCG5/ABCG8, reduction of MCP-1, and suppression of NF-kB signaling are likewise result-oriented effects of the method of Chen and Drucker.
These limitations merely recite additional molecular markers or mechanistic correlates of improved cholesterol transport and reduced inflammation that naturally accompany treatment with the same known tripeptide compounds. Because Chen in view of Drucker teaches administration of the identical peptides for the same indications (treatment of atherosclerosis) and because Applicant attributes these effects to administration of the same peptides, such recited biomarker changes are inherent effects of the known treatment or at minimum expected biological consequences thereof, even if not previously recognized in the art (see MPEP 2112).
Applicants own specification attributes these newly added limitation to administration of the same previously known tripeptides, not to any newly claimed compound, formulation, dosage regiment, or materially distinct patient population. Thus, the amendments do not define a patentably distinct method, but instead recite inherent properties and expected results of administering the known peptides.
Accordingly, Applicant’s arguments are not found persuasive, and the rejection of claim 28, 30and 38-41 under 35 U.S.C. 103 is maintained.
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 28, 30, 38-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37-38, 41-42, 50-53 of Co-pending Application 17/266897 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of treating atherosclerosis, the method comprising administering to a subject in need thereof, a therapeutically effective amount of a glycine-containing tripeptide molecule Gly-Gly-Leu or Gly-Gly-dLeu, or a pharmaceutically acceptable salt thereof, wherein the subject has atherosclerosis and does not have diabetes, wherein administering increases heaptic expression of fatty acid oxidation genes comprising PPARa and CPT1, wherein the administering reduces atherosclerotic plaque burden in the aorta, wherein the administering reduces plasma LDL cholesterol levels, wherein the administering reduces hepatic triglyceride content and hepatic total cholesterol levels in the subject”. The instant application further claims wherein the subject has CKD, stroke, atherosclerosis, PAD, CAD or aneurysm (see claim 3); and administering an additional therapeutic such as a GLP-1 or variant thereof (see claim 38). Claims 39-41 recite the following functional limitations, “wherein the administering increases expression ABCG5 and ABCG8”; wherein administering reduces plasma MCP-1 (Claim 40) and wherein administering suppresses NF-kB signaling.
Co-pending 17/266897 claims A method for treating liver disease in a mammalian subject in need thereof comprising administering to the subject at least one tripeptide selected from Gly-Gly-Leu or Gly-Gly-dLeu, or a pharmaceutically acceptable salt thereof, wherein the mammalian subject does not have diabetes, and wherein the mammalian subject has liver disease and wherein the liver disease is fatty liver, steatohepatitis, non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH).…” (claim 37). The co-pending application further claims reduction in TG (claim 41); decrease in hepatic cholesterol (claim 42); functional properties including reduction in NAS score (Claims 50-52), an additional therapeutic including GLP-1 (claim 53 ) treatment for the prevention delay or reduction in arteriosclerosis (which Applicants claim as a complication of atherosclerosis). Co-pending 17/266897 further claims administering an additional agent (claim 53).
It would have been an obvious variant of the invention claimed in the co-pending application to treat atherosclerosis. The co-pending application claims recite treating fatty liver disease in non-diabetic subjects using the same glycine containing tripeptide and further recite prevention, delay or reduction of cardiovascular complication including atherosclerosis. Because the co pending claims already encompass prevention, delay or reduction of cardiovascular complications caused by fatty liver disease, including angina, MI, stroke, arteriosclerosis and atherosclerotic related outcomes as functional result of the same treatment, a method directed to treating atherosclerosis itself represents only an obvious subset or species of the broader therapeutic use previously claimed. A person of ordinary skill would have reasonably expected that a therapy capable of reducing fatty liver associated atherosclerotic complications would also be effective for treating atherosclerosis in such subjects. Accordingly, the present claims do no define a patentably distinct use of the same peptide.
With respect to “administering increases hepatic expression of fatty acid oxidation genes PPARa and CPT1a” (claim 28) and claims 39–41, the recited increases in ABCG5/ABCG8, reduction of MCP-1, and suppression of NF-kB signaling, there are result-oriented effects of the method of Chen and Drucker.
These limitations merely recite additional molecular markers or mechanistic correlates of improved cholesterol transport and reduced inflammation that naturally accompany treatment with the same known tripeptide compounds. Because Chen in view of Drucker teaches administration of the identical peptides for the same indications (treatment of atherosclerosis) and because Applicant attributes these effects to administration of the same peptides, such recited biomarker changes are inherent effects of the known treatment or at minimum expected biological consequences thereof, even if not previously recognized in the art (see MPEP 2112).
Regarding the limitations of “reduces atherosclerotic plaque burden in the aorta, wherein the administering reduces plasma LDL cholesterol levels, wherein the administering reduces hepatic triglyceride content and hepatic total cholesterol levels in the subject”, Co-pending 17/266897 in view of Chen and Drucker teach the same method of the instant claims including administering the same peptide Gly-Gly-Leu at a therapeutically effective amount to patients with atherosclerosis and thus, these effects would necessarily occurring as result of practicing the method of Co-pending 17/266897 in view of Chen and Drucker and due to the inherent properties of Gly-Gly-Leu (see MPEP 2112).
With respect to claim 28, the limitations of administrating increases hepatic expression of fatty acid oxidation genes comprising PPARa and CPT1a, reduces atherosclerotic plaque burden in the aorta, reduces plasma LDL cholesterol, and reduces hepatic triglyceride and total cholesterol merely described biological consequences of administering the known peptide to treat the same metabolic and cardiovascular conditions including atherosclerosis. Co-pending 17/266897 in view of Chen teaches administration of the identical tripeptides for treatment of metabolic disorders associated with dyslipidemia and cardiovascular risk, while Drucker teaches that GLP-1 mediated signaling improves atherosclerosis, inflammation and lipid metabolism. Because Applicant relies on administration of the same tripeptide compounds to achieve these effects, such downstream metabolic and anti-atherogenic results would inherently accompany the prior art method, even if not previously quantified or expressly recognized (see MPEP 2112).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Applicant’s Arguments
The Applicant requests the double-patenting rejections be held in abeyance until the identification of allowable subject matter. Applicant’s request to hold the nonstatutory double patenting rejection in abeyance until identification of allowable subject matter has been considered but is not persuasive. A double patenting rejection may be properly maintained while other rejections remain pending. See MPEP § 804. Applicant may overcome the rejection by filing a terminal disclaimer, amending the claims to render them patentably distinct, or otherwise traversing the rejection on the merits. Accordingly, the request is denied and the rejection is maintained.
New Objections
Claims 28, 38-41 are objected to for the following informality: All acronyms should be spelled out in their first instance. For example, Peroxisome proliferator-activated receptor alpha (PPARα); Carnitine palmitoyltransferase I (CPT1); Angiotensin-converting enzyme (ACE); Angiotensin receptor blockers (ARBs); Glucagon Like peptide-1 (GLP-1); sodium-glucose co-transporter 2 (SGLT2); Acetyl-CoA carboxylase (ACC) etc…
New Rejections
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 28, 30, 38-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of US Patent No. 9062093 B2 in view of Chen (US20140148382 A1, cited previously) and Drucker (Cell Metabolism 24, July 12, 2016, cited previously).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of treating atherosclerosis, the method comprising administering to a subject in need thereof, a therapeutically effective amount of a glycine-containing tripeptide molecule Gly-Gly-Leu or Gly-Gly-dLeu, or a pharmaceutically acceptable salt thereof, wherein the subject has atherosclerosis and does not have diabetes, wherein administering increases heaptic expression of fatty acid oxidation genes comprising PPARa and CPT1, wherein the administering reduces atherosclerotic plaque burden in the aorta, wherein the administering reduces plasma LDL cholesterol levels, wherein the administering reduces hepatic triglyceride content and hepatic total cholesterol levels in the subject”. The instant application further claims wherein the subject has CKD, stroke, atherosclerosis, PAD, CAD or aneurysm (see claim 3); and administering an additional therapeutic such as a GLP-1 or variant thereof (see claim 38). Claims 39-41 recite the following functional limitations, “wherein the administering increases expression ABCG5 and ABCG8”; wherein administering reduces plasma MCP-1 (Claim 40) and wherein administering suppresses NF-kB signaling.
US Patent No. 9062093 B2 claims “A method for treating a condition comprising administering to a patient an effective amount of a composition, wherein the composition comprises: at least one peptide consisting of the amino acid sequence GGL” (claim 1). US Patent No. 9062093 B2 further claims “wherein the condition is prediabetes, diabetes, obesity, high blood pressure, metabolic syndrome, poor glycemic control, or reduced insulin secretion” (claim 1); wherein condition prediabetes (Claim 6); wherein the at least one peptide consists of the amino acid sequence GGL (claim 10); A method of preventing, reducing, or ameliorating a diabetes-associated complication in a diabetic patient comprising administering to the patient an effective amount of a composition (claim 12); treatment of CKD and cardiovascular disease (claim 17).
US Patent No. 9062093 B2 is silent to treating atherosclerosis and an additional therapeutic agent.
Chen teaches a method of administering a glycine tripeptide, including Gly Gly Leu (diapin) to a patient that has prediabetes, diabetes, obesity or metabolic syndrome (see claims 1, 7-12). Patients that have prediabetes, metabolic syndrome and or obesity are patients in need of preventing/treating atherosclerosis and do not necessarily have diabetes. Chen additionally teaches treating wherein the patient has chronic kidney disease (see claim 19) and coronary artery disease (see paragraph 0070). Chen additionally teaches treating the diabetes associated complication of atherosclerosis (see paragraph 0070). Chen specifically teaches that diapin stimulated GLP-1 secretion, insulin secretion and lowers blood glucose levels (see Figures 7-10). Chen teaches “The amount of the composition administered is therapeutically effective to achieve at least one of the following: reducing blood glucose levels, stimulating insulin secretion, stimulating GLP-1 secretion, reducing insulin resistance, and improving glycemic control” (see paragraph 0066). Chen teaches administering an additional therapeutic agent including a DPP-4 inhibitor (see paragraph 0075) and other diabetes drugs for treatment of diabetes, prediabetes and/or metabolic syndrome.
Although Chen does not explicitly teach treatment of atherosclerosis in an example, it recognizes that atherosclerosis as a complication of prediabetes, diabetes and metabolic syndrome and therefore implies therapeutic benefit in managing associated vascular pathologies in patients that are non-diabetic.
Drucker teaches that “Both native GLP-1 and GLP-1R agonists reduce cardiac and vascular inflammation through direct and indirect mechanisms (Figure 1). Multiple studies have demonstrated that GLP-1R agonists, including native GLP-1, exenatide (synthetic exendin-4), and liraglutide, often administered at doses that do not produce weight loss, attenuated the development of atherosclerosis in genetically sensitized murine models. These peptides reduced vascular monocyte adhesion and/or macrophage accumulation within blood vessels of several strains of normoglycemic or dysglycemic mice at high risk for the development of experimental atherosclerosis and cardiac dysfunction.” (see page 17, left column, last paragraph into right column, see also Figure 2, GLP-1 actions in the vessels, increase plaque stability, reduce platelet aggregation). Thus, Drucker attributes the anti-atherosclerotic effect to the action of GLP-1 on immune cell trafficking and inflammation.
It would have been obvious before the effective filing date of the claimed invention to treat patients with atherosclerosis with the compositions of US Patent NO. 093 (and inclusive to those without diabetes such as metabolic syndrome and prediabetes). One of ordinary skill in the art would have been motivated to do so given that improving glucose utilization, insulin sensitivity and increasing GLP-1 secretion would be beneficial in treating patients with atherosclerosis independent of diabetes as taught by Drucker. There is a reasonable expectation of success given Chen teaches treating patients with atherosclerosis as a complication with prediabetes/metabolic syndrome. Furthermore, a person of ordinary skill in the art would have been motivated to combine the teachings of US Patent NO. ‘093, Chen and Drucker and administer the peptides for the treatment of atherosclerosis, based on their known ability to stimulate GLP-1 secretion and the teaching in Drucker that GLP-1 activity reduces atherosclerotic plaque formation via modulation of immune responses. One would have a further reasonable expectation of success in using the peptides to treating atherosclerosis, even in a non-diabetic patient, given the mechanistic rationale provided in Drucker and the known effects of GLP-1 on vasculature and inflammation.
US Patent No. ‘093 does not teach specifically use the peptides in combination with GLP-1 or a synthetic variant thereof (the elected species). However, Chen does teach “Glucagon-like peptide-1 (GLP-1) is an incretin hormone. Incretin hormones are secreted by intestinal cells in response to nutrient ingestion. The primary physiological function of GLP-1 appears to be related to glycemic control. GLP-1 stimulates insulin release, inhibits glucagon secretion, reduces gastric emptying and augments satiety. Administration of GLP-1 to patients has been reported to restore blood glucose regulation via endogenous insulin secretion. GLP-1 administration has also been reported to reduce energy intake through its actions of delaying gastric emptying and increasing satiety, therefore it may induce weight loss.
MPEP states “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) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious). But see In re Geiger, 815 F.2d 686, 2 USPQ2d 1276 (Fed. Cir. 1987) (“Based upon the prior art and the fact that each of the three components of the composition used in the claimed method is conventionally employed in the art for treating cooling water systems, the board held that it would have been prima facie obvious, within the meaning of 35 U.S.C. 103, to employ these components in combination for their known functions and to optimize the amount of each additive....Appellant argues... hindsight reconstruction or at best,... obvious to try’.... We agree with appellant.”). One of ordinary skilled in the art would have been motivated to combine the two each known (GLP-1 and variants thereof with GGL, which also stimulates GLP1 naturally) to be useful for the same purpose (treating atherosclerosis in patients without diabetes such as prediabetics and metabolic syndrome), with a reasonable expectation that at least here will be an additive effect.
It would have been obvious before the effective filing date of the claimed invention to administer the peptide treatment of US Patent No. ‘093 in combination with an additional GLP-1 agent because GLP-1 receptor agonists are well known for improving glycemic control, reducing bodyweight, improving lipid parameters, and providing cardiovascular benefits in subjects with metabolic diseases and also atherosclerosis. One of ordinary skill in the art would have been motivated to combine US Patent No. ‘093 therapy with a GLP-1 agent to enhance overall therapeutic effectiveness.
Regarding the limitations of “reduces atherosclerotic plaque burden in the aorta, wherein the administering reduces plasma LDL cholesterol levels, wherein the administering reduces hepatic triglyceride content and hepatic total cholesterol levels in the subject”, US Patent No. ‘093 in view of Chen and Drucker teach the same method of the instant claims including administering the same peptide Gly-Gly-Leu at a therapeutically effective amount to patients with atherosclerosis and thus, these effects would necessarily occurring as result of practicing the method of US Patent NO. ‘093 in view of Chen and Drucker and due to the inherent properties of Gly-Gly-Leu (see MPEP 2112).
With respect to claim 28, the limitations of administrating increases hepatic expression of fatty acid oxidation genes comprising PPARa and CPT1a, reduces atherosclerotic plaque burden in the aorta, reduces plasma LDL cholesterol, and reduces hepatic triglyceride and total cholesterol merely described biological consequences of administering the known peptide to treat the same metabolic and cardiovascular conditions including atherosclerosis. US Patent NO. 093 in view of Chen teaches administration of the identical tripeptides for treatment of metabolic disorders associated with dyslipidemia and cardiovascular risk, while Drucker teaches that GLP-1 mediated signaling improves atherosclerosis, inflammation and lipid metabolism. Because Applicant relies on administration of the same tripeptide compounds to achieve these effects, such downstream metabolic and anti-atherogenic results would inherently accompany the prior art method, even if not previously quantified or expressly recognized (see MPEP 2112).
With respect to claims 39–41, the recited increases in ABCG5/ABCG8, reduction of MCP-1, and suppression of NF-kB signaling are likewise result-oriented effects of the method of US Patent NO. ‘093 in view of Chen and Drucker.
These limitations merely recite additional molecular markers or mechanistic correlates of improved cholesterol transport and reduced inflammation that naturally accompany treatment with the same known tripeptide compounds. Because US Patent NO. ‘093 in view of Chen and Drucker teaches administration of the identical peptides for the same indications (treatment of atherosclerosis) and because Applicant attributes these effects to administration of the same peptides, such recited biomarker changes are inherent effects of the known treatment or at minimum expected biological consequences thereof, even if not previously recognized in the art (see MPEP 2112).
Regarding claim 30, treatment of an atherosclerosis complication such as coronary artery disease in addition to atherosclerosis, it would have been obvious before the effective filing of the claimed invention to administer the claimed composition to a subject having atherosclerosis and a complication thereof, such as coronary artery disease. One of ordinary skill in the art would have been motivated to do so because coronary artery disease is a recognized atherosclerotic condition involving plaque accumulation in the coronary arteries. There would have been a reasonable expectation of success given that Chen teaches treatment of coronary artery disease and related metabolic cardiovascular disorders using the disclosed peptide compositions. Because coronary artery disease is a known atherosclerotic condition, one of ordinary skill in the art would have reasonably expected a therapy effective for atherosclerosis to produce similar beneficial effects in subjects with coronary artery disease.
Claims 28, 30, 38-41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of US Patent No. 8664177 B2 in view of Chen (US20140148382 A1, cited previously) and Drucker (Cell Metabolism 24, July 12, 2016, cited previously).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of treating atherosclerosis, the method comprising administering to a subject in need thereof, a therapeutically effective amount of a glycine-containing tripeptide molecule Gly-Gly-Leu or Gly-Gly-dLeu, or a pharmaceutically acceptable salt thereof, wherein the subject has atherosclerosis and does not have diabetes, wherein administering increases heaptic expression of fatty acid oxidation genes comprising PPARa and CPT1, wherein the administering reduces atherosclerotic plaque burden in the aorta, wherein the administering reduces plasma LDL cholesterol levels, wherein the administering reduces hepatic triglyceride content and hepatic total cholesterol levels in the subject”. The instant application further claims wherein the subject has CKD, stroke, atherosclerosis, PAD, CAD or aneurysm (see claim 3); and administering an additional therapeutic such as a GLP-1 or variant thereof (see claim 38). Claims 39-41 recite the following functional limitations, “wherein the administering increases expression ABCG5 and ABCG8”; wherein administering reduces plasma MCP-1 (Claim 40) and wherein administering suppresses NF-kB signaling.
US Patent No. 8664177 B2 claims “An oral pharmaceutical dosage form consisting essentially of at least one peptide consisting of the amino acid sequence GGL, GLL, GGdL, GdLL, GLdL or GdLdL, or a pharmaceutically acceptable salt of the peptide, and a pharmaceutically acceptable excipient.” (claim 1). The intended utility of US Patent No. ‘177 is treating prediabetes and metabolic syndrome (see abstract).
US Patent No. ‘177 B2 is silent to treating atherosclerosis, atherosclerosis complication and an additional therapeutic agent.
Chen teaches a method of administering a glycine tripeptide, including Gly Gly Leu (diapin) to a patient that has prediabetes, diabetes, obesity or metabolic syndrome (see claims 1, 7-12). Patients that have prediabetes, metabolic syndrome and or obesity are patients in need of preventing/treating atherosclerosis and do not necessarily have diabetes. Chen additionally teaches treating wherein the patient has chronic kidney disease (see claim 19) and coronary artery disease (see paragraph 0070). Chen additionally teaches treating the diabetes associated complication of atherosclerosis (see paragraph 0070). Chen specifically teaches that diapin stimulated GLP-1 secretion, insulin secretion and lowers blood glucose levels (see Figures 7-10). Chen teaches “The amount of the composition administered is therapeutically effective to achieve at least one of the following: reducing blood glucose levels, stimulating insulin secretion, stimulating GLP-1 secretion, reducing insulin resistance, and improving glycemic control” (see paragraph 0066). Chen teaches administering an additional therapeutic agent including a DPP-4 inhibitor (see paragraph 0075) and other diabetes drugs for treatment of diabetes, prediabetes and/or metabolic syndrome.
Although Chen does not explicitly teach treatment of atherosclerosis in an example, it recognizes that atherosclerosis as a complication of prediabetes, diabetes and metabolic syndrome and therefore implies therapeutic benefit in managing associated vascular pathologies in patients that are non-diabetic.
Drucker teaches that “Both native GLP-1 and GLP-1R agonists reduce cardiac and vascular inflammation through direct and indirect mechanisms (Figure 1). Multiple studies have demonstrated that GLP-1R agonists, including native GLP-1, exenatide (synthetic exendin-4), and liraglutide, often administered at doses that do not produce weight loss, attenuated the development of atherosclerosis in genetically sensitized murine models. These peptides reduced vascular monocyte adhesion and/or macrophage accumulation within blood vessels of several strains of normoglycemic or dysglycemic mice at high risk for the development of experimental atherosclerosis and cardiac dysfunction.” (see page 17, left column, last paragraph into right column, see also Figure 2, GLP-1 actions in the vessels, increase plaque stability, reduce platelet aggregation). Thus, Drucker attributes the anti-atherosclerotic effect to the action of GLP-1 on immune cell trafficking and inflammation.
It would have been obvious before the effective filing date of the claimed invention to treat patients with atherosclerosis with the compositions of US Patent No. ‘177 (and inclusive to those without diabetes such as metabolic syndrome and prediabetes). One of ordinary skill in the art would have been motivated to do so given that improving glucose utilization, insulin sensitivity and increasing GLP-1 secretion would be beneficial in treating patients with atherosclerosis independent of diabetes as taught by Drucker. There is a reasonable expectation of success given Chen teaches treating patients with atherosclerosis as a complication with prediabetes/metabolic syndrome. Furthermore, a person of ordinary skill in the art would have been motivated to combine the teachings of US Patent No. ‘177, Chen and Drucker and administer the peptides for the treatment of atherosclerosis, based on their known ability to stimulate GLP-1 secretion and the teaching in Drucker that GLP-1 activity reduces atherosclerotic plaque formation via modulation of immune responses. One would have a further reasonable expectation of success in using the peptides to treating atherosclerosis, even in a non-diabetic patient, given the mechanistic rationale provided in Drucker and the known effects of GLP-1 on vasculature and inflammation.
US Patent No. ‘177 does not teach specifically use the peptides in combination with GLP-1 or a synthetic variant thereof (the elected species). However, Chen does teach “Glucagon-like peptide-1 (GLP-1) is an incretin hormone. Incretin hormones are secreted by intestinal cells in response to nutrient ingestion. The primary physiological function of GLP-1 appears to be related to glycemic control. GLP-1 stimulates insulin release, inhibits glucagon secretion, reduces gastric emptying and augments satiety. Administration of GLP-1 to patients has been reported to restore blood glucose regulation via endogenous insulin secretion. GLP-1 administration has also been reported to reduce energy intake through its actions of delaying gastric emptying and increasing satiety, therefore it may induce weight loss.
MPEP states “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) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious). But see In re Geiger, 815 F.2d 686, 2 USPQ2d 1276 (Fed. Cir. 1987) (“Based upon the prior art and the fact that each of the three components of the composition used in the claimed method is conventionally employed in the art for treating cooling water systems, the board held that it would have been prima facie obvious, within the meaning of 35 U.S.C. 103, to employ these components in combination for their known functions and to optimize the amount of each additive....Appellant argues... hindsight reconstruction or at best,... obvious to try’.... We agree with appellant.”). One of ordinary skilled in the art would have been motivated to combine the two each known (GLP-1 and variants thereof with GGL, which also stimulates GLP1 naturally) to be useful for the same purpose (treating atherosclerosis in patients without diabetes such as prediabetics and metabolic syndrome), with a reasonable expectation that at least here will be an additive effect.
It would have been obvious before the effective filing date of the claimed invention to administer the peptide treatment of US Patent No. ‘177 in combination with an additional GLP-1 agent because GLP-1 receptor agonists are well known for improving glycemic control, reducing bodyweight, improving lipid parameters, and providing cardiovascular benefits in subjects with metabolic diseases and also atherosclerosis. One of ordinary skill in the art would have been motivated to combine US Patent No. ‘177 therapy with a GLP-1 agent to enhance overall therapeutic effectiveness.
Regarding the limitations of “reduces atherosclerotic plaque burden in the aorta, wherein the administering reduces plasma LDL cholesterol levels, wherein the administering reduces hepatic triglyceride content and hepatic total cholesterol levels in the subject”, US Patent No. ‘177 in view of Chen and Drucker teach the same method of the instant claims including administering the same peptide Gly-Gly-Leu at a therapeutically effective amount to patients with atherosclerosis and thus, these effects would necessarily occurring as result of practicing the method of US Patent No. ‘177 in view of Chen and Drucker and due to the inherent properties of Gly-Gly-Leu (see MPEP 2112).
With respect to claim 28, the limitations of administrating increases hepatic expression of fatty acid oxidation genes comprising PPARa and CPT1a, reduces atherosclerotic plaque burden in the aorta, reduces plasma LDL cholesterol, and reduces hepatic triglyceride and total cholesterol merely described biological consequences of administering the known peptide to treat the same metabolic and cardiovascular conditions including atherosclerosis. US Patent No. ‘177 in view of Chen teaches administration of the identical tripeptides for treatment of metabolic disorders associated with dyslipidemia and cardiovascular risk, while Drucker teaches that GLP-1 mediated signaling improves atherosclerosis, inflammation and lipid metabolism. Because Applicant relies on administration of the same tripeptide compounds to achieve these effects, such downstream metabolic and anti-atherogenic results would inherently accompany the prior art method, even if not previously quantified or expressly recognized (see MPEP 2112).
With respect to claims 39–41, the recited increases in ABCG5/ABCG8, reduction of MCP-1, and suppression of NF-kB signaling are likewise result-oriented effects of the method of US Patent No. ‘177 in view of Chen and Drucker.
These limitations merely recite additional molecular markers or mechanistic correlates of improved cholesterol transport and reduced inflammation that naturally accompany treatment with the same known tripeptide compounds. Because US Patent No. ‘177 in view of Chen and Drucker teaches administration of the identical peptides for the same indications (treatment of atherosclerosis) and because Applicant attributes these effects to administration of the same peptides, such recited biomarker changes are inherent effects of the known treatment or at minimum expected biological consequences thereof, even if not previously recognized in the art (see MPEP 2112).
Regarding claim 30, treatment of an atherosclerosis complication such as coronary artery disease in addition to atherosclerosis, it would have been obvious before the effective filing of the claimed invention to administer the claimed composition to a subject having atherosclerosis and a complication thereof, such as coronary artery disease. One of ordinary skill in the art would have been motivated to do so because coronary artery disease is a recognized atherosclerotic condition involving plaque accumulation in the coronary arteries. There would have been a reasonable expectation of success given that Chen teaches treatment of coronary artery disease and related metabolic cardiovascular disorders using the disclosed peptide compositions. Because coronary artery disease is a known atherosclerotic condition, one of ordinary skill in the art would have reasonably expected a therapy effective for atherosclerosis to produce similar beneficial effects in subjects with coronary artery disease.
Claims 28, 30, 38-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14, 53-64 of Co-pending 18/020908 in view of Chen (US20140148382 A1, cited previously) and Drucker (Cell Metabolism 24, July 12, 2016, cited previously).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims “A method of treating atherosclerosis, the method comprising administering to a subject in need thereof, a therapeutically effective amount of a glycine-containing tripeptide molecule Gly-Gly-Leu or Gly-Gly-dLeu, or a pharmaceutically acceptable salt thereof, wherein the subject has atherosclerosis and does not have diabetes, wherein administering increases heaptic expression of fatty acid oxidation genes comprising PPARa and CPT1, wherein the administering reduces atherosclerotic plaque burden in the aorta, wherein the administering reduces plasma LDL cholesterol levels, wherein the administering reduces hepatic triglyceride content and hepatic total cholesterol levels in the subject”. The instant application further claims wherein the subject has CKD, stroke, atherosclerosis, PAD, CAD or aneurysm (see claim 3); and administering an additional therapeutic such as a GLP-1 or variant thereof (see claim 38). Claims 39-41 recite the following functional limitations, “wherein the administering increases expression ABCG5 and ABCG8”; wherein administering reduces plasma MCP-1 (Claim 40) and wherein administering suppresses NF-kB signaling.
Co-pending AN 18/020908 claims “AA method of treating steatohepatitis in a subject, comprising administering a pharmaceutically effective amount of at least one N-acyl amino acid product to the subject, wherein the N-acyl amino acid product has a fatty acid component and an amino acid” (claim 14). Copending AN 18/020908 further claims wherein the amino acid component is glycine- glycine-leucine or glycine-glycine-D-leucine (Claim 58); wherein the treating results in the subject in decreased liver fat, decreased inflammatory status, decreased injured hepatocytes and decreased atherosclerotic plaques (claim 63) which suggests treating atherosclerosis.
Co-pending AN 18/020908 is silent to treating atherosclerosis without diabetes, atherosclerosis complication and an additional therapeutic agent.
However, Chen teaches a method of administering a glycine tripeptide, including Gly Gly Leu (diapin) to a patient that has prediabetes, diabetes, obesity or metabolic syndrome (see claims 1, 7-12). Patients that have prediabetes, metabolic syndrome and or obesity are patients in need of preventing/treating atherosclerosis and do not necessarily have diabetes. Chen additionally teaches treating wherein the patient has chronic kidney disease (see claim 19) and coronary artery disease (see paragraph 0070). Chen additionally teaches treating the diabetes associated complication of atherosclerosis (see paragraph 0070). Chen specifically teaches that diapin stimulated GLP-1 secretion, insulin secretion and lowers blood glucose levels (see Figures 7-10). Chen teaches “The amount of the composition administered is therapeutically effective to achieve at least one of the following: reducing blood glucose levels, stimulating insulin secretion, stimulating GLP-1 secretion, reducing insulin resistance, and improving glycemic control” (see paragraph 0066). Chen teaches administering an additional therapeutic agent including a DPP-4 inhibitor (see paragraph 0075) and other diabetes drugs for treatment of diabetes, prediabetes and/or metabolic syndrome.
Although Chen does not explicitly teach treatment of atherosclerosis in an example, it recognizes that atherosclerosis as a complication of prediabetes, diabetes and metabolic syndrome and therefore implies therapeutic benefit in managing associated vascular pathologies in patients that are non-diabetic.
Drucker teaches that “Both native GLP-1 and GLP-1R agonists reduce cardiac and vascular inflammation through direct and indirect mechanisms (Figure 1). Multiple studies have demonstrated that GLP-1R agonists, including native GLP-1, exenatide (synthetic exendin-4), and liraglutide, often administered at doses that do not produce weight loss, attenuated the development of atherosclerosis in genetically sensitized murine models. These peptides reduced vascular monocyte adhesion and/or macrophage accumulation within blood vessels of several strains of normoglycemic or dysglycemic mice at high risk for the development of experimental atherosclerosis and cardiac dysfunction.” (see page 17, left column, last paragraph into right column, see also Figure 2, GLP-1 actions in the vessels, increase plaque stability, reduce platelet aggregation). Thus, Drucker attributes the anti-atherosclerotic effect to the action of GLP-1 on immune cell trafficking and inflammation.
It would have been obvious before the effective filing date of the claimed invention to treat patients with atherosclerosis with the compositions of Copending AN 18/020908 (and inclusive to those without diabetes such as metabolic syndrome and prediabetes). One of ordinary skill in the art would have been motivated to do so given that improving glucose utilization, insulin sensitivity and increasing GLP-1 secretion would be beneficial in treating patients with atherosclerosis independent of diabetes as taught by Drucker. There is a reasonable expectation of success given Chen teaches treating patients with atherosclerosis as a complication with prediabetes/metabolic syndrome. Furthermore, a person of ordinary skill in the art would have been motivated to combine the teachings of Copending AN 18/020908, Chen and Drucker and administer the peptides for the treatment of atherosclerosis, based on their known ability to stimulate GLP-1 secretion and the teaching in Drucker that GLP-1 activity reduces atherosclerotic plaque formation via modulation of immune responses. One would have a further reasonable expectation of success in using the peptides to treating atherosclerosis, even in a non-diabetic patient, given the mechanistic rationale provided in Drucker and the known effects of GLP-1 on vasculature and inflammation.
Copending AN 18/020908 does not teach specifically use the peptides in combination with GLP-1 or a synthetic variant thereof (the elected species). However, Chen does teach “Glucagon-like peptide-1 (GLP-1) is an incretin hormone. Incretin hormones are secreted by intestinal cells in response to nutrient ingestion. The primary physiological function of GLP-1 appears to be related to glycemic control. GLP-1 stimulates insulin release, inhibits glucagon secretion, reduces gastric emptying and augments satiety. Administration of GLP-1 to patients has been reported to restore blood glucose regulation via endogenous insulin secretion. GLP-1 administration has also been reported to reduce energy intake through its actions of delaying gastric emptying and increasing satiety, therefore it may induce weight loss.
MPEP states “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) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious). But see In re Geiger, 815 F.2d 686, 2 USPQ2d 1276 (Fed. Cir. 1987) (“Based upon the prior art and the fact that each of the three components of the composition used in the claimed method is conventionally employed in the art for treating cooling water systems, the board held that it would have been prima facie obvious, within the meaning of 35 U.S.C. 103, to employ these components in combination for their known functions and to optimize the amount of each additive....Appellant argues... hindsight reconstruction or at best,... obvious to try’.... We agree with appellant.”). One of ordinary skilled in the art would have been motivated to combine the two each known (GLP-1 and variants thereof with GGL, which also stimulates GLP1 naturally) to be useful for the same purpose (treating atherosclerosis in patients without diabetes such as prediabetics and metabolic syndrome or steatohepatitis), with a reasonable expectation that at least here will be an additive effect.
It would have been obvious before the effective filing date of the claimed invention to administer the peptide treatment of Copending AN 18/020908 in combination with an additional GLP-1 agent because GLP-1 receptor agonists are well known for improving glycemic control, reducing bodyweight, improving lipid parameters, and providing cardiovascular benefits in subjects with metabolic diseases (fatty liver) and also atherosclerosis. One of ordinary skill in the art would have been motivated to combine Copending AN 18/020908 therapy with a GLP-1 agent to enhance overall therapeutic effectiveness.
Regarding the limitations of “reduces atherosclerotic plaque burden in the aorta, wherein the administering reduces plasma LDL cholesterol levels, wherein the administering reduces hepatic triglyceride content and hepatic total cholesterol levels in the subject”, Copending AN 18/020908 in view of Chen and Drucker teach the same method of the instant claims including administering the same peptide Gly-Gly-Leu at a therapeutically effective amount to patients with atherosclerosis and thus, these effects would necessarily occurring as result of practicing the method of Copending AN 18/020908 in view of Chen and Drucker and due to the inherent properties of Gly-Gly-Leu (see MPEP 2112).
With respect to claim 28, the limitations of administrating increases hepatic expression of fatty acid oxidation genes comprising PPARa and CPT1a, reduces atherosclerotic plaque burden in the aorta, reduces plasma LDL cholesterol, and reduces hepatic triglyceride and total cholesterol merely described biological consequences of administering the known peptide to treat the same metabolic and cardiovascular conditions including atherosclerosis. Copending AN 18/020908 in view of Chen teaches administration of the identical tripeptides for treatment of metabolic disorders associated with dyslipidemia and cardiovascular risk, while Drucker teaches that GLP-1 mediated signaling improves atherosclerosis, inflammation and lipid metabolism. Because Applicant relies on administration of the same tripeptide compounds to achieve these effects, such downstream metabolic and anti-atherogenic results would inherently accompany the prior art method, even if not previously quantified or expressly recognized (see MPEP 2112).
With respect to claims 39–41, the recited increases in ABCG5/ABCG8, reduction of MCP-1, and suppression of NF-kB signaling are likewise result-oriented effects of the method of Copending AN 18/020908 in view of Chen and Drucker.
These limitations merely recite additional molecular markers or mechanistic correlates of improved cholesterol transport and reduced inflammation that naturally accompany treatment with the same known tripeptide compounds. Because Copending AN 18/020908 in view of Chen and Drucker teaches administration of the identical peptides for the same indications (treatment of atherosclerosis) and because Applicant attributes these effects to administration of the same peptides, such recited biomarker changes are inherent effects of the known treatment or at minimum expected biological consequences thereof, even if not previously recognized in the art (see MPEP 2112).
Regarding claim 30, treatment of an atherosclerosis complication such as coronary artery disease in addition to atherosclerosis, it would have been obvious before the effective filing of the claimed invention to administer the claimed composition of Copending AN 18/020908 to a subject having atherosclerosis and a complication thereof, such as coronary artery disease. One of ordinary skill in the art would have been motivated to do so because coronary artery disease is a recognized atherosclerotic condition involving plaque accumulation in the coronary arteries. There would have been a reasonable expectation of success given that Chen teaches treatment of coronary artery disease and related metabolic cardiovascular disorders using the disclosed peptide compositions. Because coronary artery disease is a known atherosclerotic condition, one of ordinary skill in the art would have reasonably expected a therapy effective for atherosclerosis to produce similar beneficial effects in subjects with coronary artery disease.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 Est.
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, Lianko Garyu can be reached at 571-270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERINNE R DABKOWSKI/Examiner, Art Unit 1654
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