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 .
Election/Restrictions
Applicant's election with traverse of Group I in the reply filed on 06/19/2026 is acknowledged. The traversal is on the ground(s) that the pending claims are directed to a single inventive concept involving modulation of SNAT2 for treatment of hypertension, that the grouped inventions share a common utility and are capable of use together, that the identified inventions are not patentably distinct, and that the asserted search and examination burden has not been established. This is not found persuasive because while the pending claims generally relate to modulation of SNAT2, the restriction requirement is based on the claimed inventions as presented, not on the existence of a common biological target or overall research objective. The identified groups are properly treated as related but distinct inventions under the applicable provisions of MPEP § 806.05 because they are directed to materially different statutory inventions, including therapeutic methods, methods of preparing genetically modified cells, genetically modified cell products, and drug-screening methods. These inventions differ in their claimed subject matter, function, and mode of operation, require materially different examination and search, and do not merely represent different claim scope of the same invention. Applicant’s arguments have not demonstrated that the restriction requirement was improper.
However, after further consideration, the Examiner has decided to withdraw the requirement for electing within the species of SNAT2 inhibition.
The requirement between Groups I-IV is still deemed proper and is therefore made FINAL.
Claims 16-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Status of Claims
Claims 11-18 are currently pending.
Claims 11-15 are under consideration, as claims 16-18 are withdrawn.
Priority
The present application is a continuation of PCT/CN2023/111949 filed on 08/09/2023. Acknowledgment is made of applicant' s claim for foreign priority and papers submitted under 35 U.S.C. 119 (a)-(d). The present application claims the benefit of the earliest effective filing date to Chinese application CN2022111562 and all claims are being examined with an effective filing date of 09/22/2022. Please note that the Chinese application is in a foreign language and therefore cannot be reviewed. In future actions, the effective filing date may change due to amendments or further review of priority documents.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/19/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Objections
Claims 14 and 15 are objected to because of the following informalities:
Claim 14 is objected to because the phrase “is drug of small nucleic acid” lacks an article and is grammatically incomplete. Appropriate correction is required (for example, “is a drug…” or equivalent language).
Claim 15 is objected to because the phrase “wherein the method can… lowering… preventing… promoting…” is grammatically inconsistent. Appropriate correction is required so that the verb forms are grammatically consistent (for example, “can lower… prevent… promote…” or equivalent language).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 11-15 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 11-15 are indefinite due to the recitation of a method for preventing and/or treating primary hypertension and its “relevant disorders.” The metes and bounds of the term “relevant disorders” are unclear because the claims do not provide an objective standard for determining which disorders are considered “relevant” to primary hypertension. It is unclear, for example, whether the term encompasses only disorders directly caused by primary hypertension, disorders for which primary hypertension is a risk factor, complications that may be aggravated by primary hypertension, disorders that may be ameliorated by lowering blood pressure, or any cardiovascular, cerebrovascular, renal, pulmonary or other disorder associated in some manner with hypertension.
The specification does not resolve this ambiguity. Paragraph [0002] states that hypertension can lead to complications including cerebral hemorrhage, cerebral infarction, fundus blindness, myocardial infarction, and kidney disease. Paragraph [0003] further states that prolonged hypertension and accompanying risk factors may promote atherosclerosis and ultimately lead to coronary heart disease, including angina pectoris and myocardial infarction, and stroke. Paragraphs [0010]–[0012] identify angina pectoris, myocardial infarction, and stroke as examples of “relevant disorders,” but expressly follow those conditions with “etc.” Thus, the specification provides examples of conditions that may be associated with or arise as complications of hypertension, but does not define the objective boundaries of the claimed category or provide a standard by which a person of ordinary skill in the art could determine whether any additional disorder falls within or outside the scope of “relevant disorders.”
Claim 13 is included in this rejection because although claim 13 recites that the relevant disorder “comprises angina pectoris, myocardial infarction and stroke,” the open-ended transitional term “comprises” does not limit the claimed relevant disorders exclusively to those three identified conditions. Accordingly, claim 13 does not resolve which additional disorders may be encompassed by the term “relevant disorders,” and the scope of the claim remains unclear.
Therefore, one of ordinary skill in the art would not be able to determine the metes and bounds of the claimed “relevant disorders” with reasonable certainty. For purposes of examination and in the interest of advancing prosecution, the Examiner interprets “relevant disorders” as encompassing disorders that are caused by, arise as complications of, or are exacerbated by primary hypertension, including, but not limited to, angina pectoris, myocardial infarction, and stroke.
Additionally, claims 11-15 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for attempting to claim a process without setting forth any steps involved in the process. Merely reciting a use without any active, positive steps delimiting how this use is actually practiced, renders the claim indefinite (see MPEP 2173. 05(q)).
Additionally, claim 15 is further indefinite due to the recitation of “wherein the method can” because it is unclear whether the claim requires that the recited method actually lowers blood pressure, prevents and/or treats hypertension, and promotes production of nitric oxide (NO), or merely possesses the capability of doing so. Moreover, to the extent the claim is intended to encompass mere capability, the claim fails to provide an objective standard by which one of ordinary skill in the art could determine whether a particular method possesses such capability. Accordingly, the metes and bounds of the claim are unclear. Because the examiner cannot determine whether claim 15 requires actual performance or merely the capability of performing the recited functions, nor determine the standard by which such capability is evaluated or determined, the scope of the claim cannot be reasonably ascertained for purposes of evaluating the additional limitation under the prior art.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 11-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
During examination, the claims are given their broadest reasonable interpretation consistent with the specification. Claim 11 is broadly interpreted as encompassing a genus of methods for preventing and/or treating primary hypertension and a genus of related disorders, as defined above, using a genus of SNAT2-modulating substances, including any SNAT2 competitive inhibitor, any substance having SNAT2 competitive inhibitory activity, any substance having inhibitory activity against the SNAT2 gene or its gene products, including SNAT2 mRNA or protein, and any substance capable of knocking out or silencing the SNAT2 gene. The claim is not limited by the structure, sequence, mechanism, potency, selectivity, route of administration, dosage, formulation, degree of SNAT2 inhibition, tissue targeted, or particular manner in which the substance prevents or treats the claimed disease or disorder.
MPEP 2163 I. states that to “satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.
MPEP 2163. II.A.3.(a) states that “Possession may be shown in many ways. For example, possession may be shown by describing an actual reduction to practice of the claimed invention. Possession may also be shown by a clear depiction of the invention in detailed drawings or in structural chemical formulas which permit a person skilled in the art to clearly recognize that inventor had possession of the claimed invention. An adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics so long as a person skilled in the art would recognize that the inventor had possession of the claimed invention.
In the instant case, the specification does not disclose a representative number of substances falling within the several functional genera recited in claim 11, nor does it disclose common structural characteristics sufficient to identify the members of those genera. With respect to the claimed SNAT2 competitive inhibitors and substances having SNAT2 competitive inhibitory activity, the specification identifies only one specific compound, α-aminoisobutyric acid, also referred to as MeAIB. Paragraph [0013] states that the substance having SNAT2 competitive inhibitory activity “may specifically be” MeAIB. Paragraphs [0035]–[0037] describe MeAIB as a competitive inhibitor of SNAT2, and Example 1 at paragraphs [0053]–[0055] administers MeAIB to wild-type mice in drinking water at 1 g/L for two weeks and reports a decrease in systolic blood pressure. Example 6 at paragraphs [0068]–[0070] further reports that MeAIB increased nitric-oxide content and eNOS-related activity in cultured human umbilical-vein endothelial cells. However, the specification does not identify any additional structurally distinct SNAT2 competitive inhibitor or any additional substance having SNAT2 competitive inhibitory activity. The specification provides no chemical genus, structural formula, pharmacophore, binding-site characterization, structure-activity relationship, or other identifying structural feature shared by substances expected to possess the claimed competitive inhibitory activity. It also does not provide a correlation by which the structure of a substance would allow one of ordinary skill to recognize that the substance falls within the claimed genus. Accordingly, the disclosure of MeAIB, standing alone, does not reasonably convey possession of the full genus of all SNAT2 competitive inhibitors or all substances having SNAT2 competitive inhibitory activity encompassed by claim 11.
The specification similarly fails to disclose a representative number of substances having inhibitory activity against the SNAT2 gene and its products, including SNAT2 mRNA and protein. Paragraphs [0011], [0012], [0019], and [0024] restate the desired function of inhibiting SNAT2 expression, mRNA, protein, or gene activity, but do not identify a particular therapeutic molecule having those functions. The specification does not provide, for example, an antisense sequence, siRNA sequence, microRNA sequence, aptamer sequence, targeting region of the SNAT2 gene or transcript, nucleotide length, chemical modification, vector, promoter, delivery vehicle, endothelial-targeting moiety, or other structural characteristic identifying a substance falling within the claimed genus. Nor does the specification provide experimental data showing that any administered gene-expression inhibitor reduces SNAT2 mRNA or protein, reaches vascular endothelial cells in vivo, lowers blood pressure, prevents hypertension, or treats any claimed disorder. Merely stating the desired result—that a substance inhibit SNAT2 gene expression, mRNA, or protein—does not describe the structural or other identifying features of the substances that achieve that result and therefore does not reasonably convey possession of the claimed functional genus.
Regarding substances capable of knocking out or silencing SNAT2, the specification does describe genetically engineered mouse models in which SNAT2 was deleted. Example 2 at paragraphs [0056]–[0058] describes systemic SNAT2-knockout mice produced using CRISPR/Cas9 deletion of 10 base pairs in exon 4. Example 3 at paragraphs [0059]–[0061] describes endothelial-specific SNAT2-knockout mice produced using floxed SNAT2 alleles and vascular endothelial-specific Cre mice. Examples 4 and 5 at paragraphs [0062]–[0067] further report resistance to high-salt-diet-induced elevation of systolic blood pressure and increased serum nitric oxide in SNAT2-knockout mice. These genetically engineered animal models provide evidence concerning the biological consequences of the absence of SNAT2. They do not, however, identify or describe a therapeutic “substance” capable of knocking out or silencing SNAT2 when used to prevent or treat hypertension in a subject. The specification does not disclose a guide-RNA sequence, therapeutic CRISPR construct, nuclease-delivery system, vector, dose, formulation, route of administration, tissue-targeting mechanism, or in vivo treatment protocol by which SNAT2 is knocked out or silenced in an existing subject. Moreover, germline or developmentally produced knockout mice are not representative of the broad genus of therapeutic substances capable of knocking out or silencing SNAT2 in a patient. The disclosure therefore does not reasonably convey possession of the full scope of the claimed knockout-or-silencing-substance genus.
Regarding the scope of preventing and treating primary hypertension and “relevant disorders”, the actual therapeutic evidence is substantially narrower than the claimed genus of disorders. Example 1 demonstrates administration of MeAIB to wild-type mice and reports reduced basal systolic blood pressure. Examples 2 and 3 report lower basal blood pressure in genetically engineered SNAT2-knockout mice. Example 4 reports that knockout mice were resistant to an increase in systolic blood pressure caused by a high-salt diet. Example 5 reports increased serum nitric oxide in knockout mice, and Example 6 reports increased nitric-oxide production and eNOS-related activity in cultured endothelial cells treated with MeAIB. The specification contains no working example involving an animal or human subject having established primary hypertension that is treated using MeAIB or any other administered SNAT2-modulating substance. More significantly, it contains no working or prophetic example showing prevention or treatment of angina pectoris, myocardial infarction, stroke, cerebral hemorrhage, cerebral infarction, kidney disease, fundus blindness, or any other purported “relevant disorder.” The general statements at paragraphs [0002]–[0004] that hypertension may cause such complications and that reductions in blood pressure are associated with reductions in cardiovascular events do not demonstrate that the inventors possessed methods of preventing or treating each such disorder through the full range of claimed SNAT2-modulating substances. The disclosure therefore provides, at most, possession of a considerably narrower concept involving the effect of MeAIB or genetically engineered loss of SNAT2 on basal blood pressure, salt-induced blood-pressure elevation, and nitric-oxide production. It does not reasonably convey possession of the claimed genus of methods using all functionally defined classes of SNAT2 inhibitors, expression inhibitors, knockout agents, and silencing agents to prevent or treat primary hypertension and the full genus of claimed relevant disorders.
Accordingly, the specification fails to reasonably convey possession of the claimed inventions commensurate in scope with claims 11–15, and the claims are rejected for lack of written description.
Claims 11-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the use of MeAIB and genetically engineered SNAT2-knockout mouse models, does not reasonably enable the full scope of the claimed methods encompassing prevention and/or treatment of primary hypertension and any relevant disorders using any SNAT2 competitive inhibitor, any substance having SNAT2 competitive inhibitory activity, any substance having inhibitory activity against the SNAT2 gene or its products, or any substance capable of knocking out or silencing the SNAT2 gene. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The specification fails to enable the claims (or the full scope of the claims) if a person of ordinary skill in the art would be faced with an undue burden of experimentation when trying to implement the invention based on the disclosure. In re Wands (858 F.2d 731 at 737, 8 USPQ2d 1400 at 1404 (Fed. Cir. 1988)) sets forth a non-exclusive list of factors by which this burden of experimentation may be judged to be due or undue; factors that are germane to the instant case include the breadth of the claims, nature of the invention, the amount of direction provided by the inventor, the existence of working examples and the state of the prior art.
Claim 11 broadly encompasses methods for preventing and/or treating primary hypertension and a genus of relevant disorders by administering any agent that competitively inhibits SNAT2, possesses SNAT2 competitive inhibitory activity, inhibits expression of the SNAT2 gene or its products, or knocks out or silences the SNAT2 gene, including but not limited to antisense oligonucleotides, siRNAs, microRNAs, aptamers, and other gene-targeting molecules. The therapeutic scope likewise extends beyond primary hypertension to angina pectoris, myocardial infarction, stroke, and a vast array of relevant disorders, as defined above (see 112b). Accordingly, the nature of the invention and breadth of the claims encompass numerous distinct classes of therapeutic agents related to SNAT2, employing different mechanisms of action, any delivery strategies, having numerous pharmacological properties, for numerous therapeutic applications related to hypertension.
Although the specification provides experimental protocols for administration of MeAIB and evaluation of genetically engineered knockout animals, it provides little guidance for practicing the remainder of the claimed genus. The specification provides no guidance for determining which of the innumerable candidate agents falling within the scope of the claims would actually be effective for preventing and/or treating primary hypertension or the broad genus of hypertension related disorders. Nor does the disclosure teach how to identify additional operative SNAT2 competitive inhibitors, determine whether candidate compounds possess sufficient SNAT2 competitive inhibitory activity, design or select effective antisense oligonucleotides, siRNAs, microRNAs, aptamers, or other gene-silencing agents, identify suitable target sequences, develop delivery systems for such agents, determine therapeutically effective dosages or formulations, or evaluate efficacy and safety for the broad range of claimed cardiovascular disorders. Accordingly, the specification provides insufficient guidance for practicing the full scope of the claims.
The working examples are limited to administration of MeAIB in mice, experiments utilizing genetically engineered SNAT2 knockout mice, measurements of blood pressure and nitric oxide production, vascular function studies, and in vitro endothelial cell experiments. The specification contains no working examples utilizing additional SNAT2 competitive inhibitors, antisense oligonucleotides, siRNAs, microRNAs, aptamers, or other gene-targeting agents. Likewise, no working examples demonstrate prevention or treatment of angina pectoris, myocardial infarction, stroke, or other relevant disorders recited in the claims. Thus, the working examples are not representative of the full breadth of the claimed invention.
With respect to the state of the prior art, the art recognized the biological role of SNAT2 and identified certain approaches for inhibiting SNAT2 activity. For example, as evidenced by “Coles” (relied upon in the § 103 rejection below), SNAT2 was known to function as a glutamine transporter, and MeAIB was recognized as a competitive inhibitor of SNAT1/2. However, the prior art did not establish that the broad classes of agents recited in the present claims—including any SNAT2 competitive inhibitor, any substance having SNAT2 competitive inhibitory activity, any substance having inhibitory activity against the SNAT2 gene or its products, or any agent capable of knocking out or silencing the SNAT2 gene—could generally be identified, developed, and successfully applied to prevent and/or treat primary hypertension and the full scope of the claimed hypertension-related disorders without undue experimentation. Rather, the prior art reflects that substantial research remained necessary to identify effective agents, achieve selective inhibition, optimize delivery, minimize off-target effects, and demonstrate therapeutic efficacy across the full scope of the claimed methods. Accordingly, the state of the prior art weighs against enablement across the full scope of the claims.
To practice the full scope of the claimed invention, one of ordinary skill in the art would be required to identify and screen additional SNAT2 inhibitors, develop and validate gene-targeting agents, determine appropriate target sequences, optimize delivery systems, establish therapeutically effective formulations, dosages, and routes of administration, evaluate safety and off-target effects, and determine efficacy across the broad range of claimed disease indications. Such work would require extensive research and experimentation beyond routine optimization of the limited embodiments disclosed in the specification.
Accordingly, in view of the breadth of the claims, the limited guidance provided by the specification, the absence of representative working examples, the unpredictability of the art, and the extensive experimentation necessary to practice the full scope of the claimed invention, one of ordinary skill in the art would not have been able to make and use the claimed invention commensurate in scope with claims 11-15 without undue experimentation. Therefore, claims 11-15 are rejected under 35 U.S.C. § 112(a) for lack of enablement.
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.
Claims 11-14 are rejected under 35 U.S.C. §103 as being unpatentable over Mprah et al. (Glutaminolysis: A Driver of Vascular and Cardiac Remodeling in Pulmonary Arterial Hypertension. Front. Cardiovasc. Med. 8:667446, herein “Mprah”, cited in PTO-892)and Gauthier-Coles et al. (Identification and characterization of a novel SNAT2 (SLC38A2) inhibitor reveals synergy with glucose transport inhibition in cancer cells. Front Pharmacol. 2022 Sep 21;13:963066, herein “Coles”, cited in the IDS).
Regarding claim 11, Mprah teaches that dysregulated glutamine metabolism and increased glutaminolysis contribute to pathological vascular remodeling by producing hyperproliferative and apoptosis-resistant vascular-cell phenotypes and promoting endothelial dysfunction, fibrosis, angiogenesis, endothelial-cell proliferation, smooth-muscle-cell proliferation, vessel stiffening, and extracellular matrix remodeling (pg. 2–3). Mprah further teaches that increased glutaminolysis replenishes tricarboxylic-acid-cycle intermediates required to support the energy and biomass demands of rapidly proliferating vascular cells and is associated with increased glutaminase-1 expression and increased glutamine uptake (pg. 3). Mprah additionally teaches that extracellular matrix stiffness induces glutaminase-1 expression, stimulates endothelial- and smooth-muscle-cell proliferation, and promotes collagen stabilization, arterial stiffening, and vascular remodeling through glutaminolysis. Mprah further teaches that pharmacological inhibition of glutaminase-1 interrupts this pathogenic pathway, diminishes arterial remodeling in monocrotaline-induced pulmonary arterial hypertension in rats, prevents pulmonary arterial hypertension in BMPR2-mutant mice when glutamine metabolism is normalized, and concludes that therapeutic targeting of glutamine metabolism represents a promising treatment strategy (pg. 3). Mprah further teaches that increased glutamine uptake is observed in both human patients and animal models and that inhibition of glutaminolytic-pathway components ameliorates disease progression, thereby teaching that therapeutic intervention may be directed toward glutamine metabolism beginning with glutamine uptake and extending through downstream glutaminolytic reactions (pg. 5). Accordingly, Mprah teaches that therapeutic interruption of glutamine uptake and glutaminolysis targets the underlying pathogenic mechanism responsible for vascular remodeling. Thus, one of ordinary skill in the art would have recognized from Mprah that modulation of glutamine metabolism constitutes a promising therapeutic approach for diseases involving pathological vascular remodeling. However, Mprah does not expressly teach treating primary hypertension using a competitive SNAT2 inhibitor, a substance having SNAT2 inhibitory activity or capable of knocking out or silencing the SNAT2 gene.
Coles teaches that SNAT2 is a sodium-dependent neutral amino-acid transporter responsible for maintaining intracellular amino-acid pools, activating mTORC1, and providing net glutamine for the glutaminolysis pathway, thereby identifying SNAT2 as a therapeutic target (pg. 1–2). Coles further teaches that N-methylaminoisobutyric acid (MeAIB) is a known competitive inhibitor of SNAT1/2 and experimentally demonstrates that MeAIB substantially inhibits SNAT1/2-mediated glutamine uptake in amino-acid-depleted cells, thereby reducing intracellular glutamine available for glutaminolysis (pg. 2 and 6–7).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to utilize the known SNAT2 competitive inhibitor taught by Coles in the therapeutic strategy taught by Mprah. Mprah teaches that pathological glutamine uptake and glutaminolysis drive the metabolic pathway responsible for endothelial dysfunction, fibrosis, hyperproliferation, arterial stiffening, and pathological vascular remodeling, and further teaches that therapeutic interruption of glutamine metabolism beginning with glutamine uptake is a promising approach for reducing those pathological processes. Coles supplies the missing teaching by identifying SNAT2 as the upstream transporter responsible for providing intracellular glutamine for glutaminolysis and by teaching a known competitive inhibitor, MeAIB, capable of inhibiting SNAT2-mediated glutamine transport. Accordingly, one of ordinary skill in the art would have been motivated to employ the known SNAT2 competitive inhibitor taught by Coles as the pharmacological means for interrupting the glutamine-dependent metabolic pathway identified by Mprah, thereby reducing intracellular glutamine availability for glutaminolysis and interrupting the pathogenic cascade leading to endothelial dysfunction, fibrosis, hyperproliferation, arterial stiffening, and vascular remodeling. Although the evidence reviewed by Mprah was obtained in pulmonary arterial hypertension, Mprah attributes the observed vascular pathology and therapeutic benefit to metabolic mechanisms involving glutamine uptake, glutaminolysis, endothelial- and smooth-muscle-cell proliferation, fibrosis, and vascular remodeling, rather than to a mechanism unique to the pulmonary circulation. Therefore, one of ordinary skill in the art would have recognized that the therapeutic strategy taught by Mprah is directed to interruption of a pathogenic metabolic pathway rather than treatment of a pulmonary-specific physiological process. Because Coles teaches a specific pharmacological means for interrupting that same pathway through inhibition of SNAT2-mediated glutamine uptake, it would have been obvious to apply that mechanism-directed therapeutic strategy to the treatment of primary hypertension. There is a reasonable expectation of success that SNAT2 inhibition could prevent and/or treat primary hypertension and relevant disorders because Mprah reviews experimental evidence demonstrating that interruption of glutamine metabolism diminishes arterial remodeling and ameliorates disease progression, while Coles experimentally identifies MeAIB as substantially inhibiting SNAT1/2-mediated glutamine uptake. Together, Mprah and Coles provide both a recognized therapeutic objective—interrupting the pathogenic glutaminolytic pathway underlying vascular remodeling—and a known pharmacological means for achieving that objective through competitive inhibition of SNAT2-mediated glutamine uptake. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention.
Regarding claim 12, Coles expressly teaches the known SNAT2 competitive inhibitor N-methylaminoisobutyric acid (MeAIB) for inhibition of SNAT2-mediated transport (pg. 2).
Regarding claim 13, as discussed above, it would have been obvious to utilize a SNAT2 competitive inhibitor to treat primary hypertension by inhibiting the glutaminolytic pathway implicated in pathological vascular remodeling. The instant specification identifies angina pectoris, myocardial infarction, and stroke as examples of “relevant disorders” associated with primary hypertension. Because these disorders are recognized as disorders that result from, are exacerbated by, or are complications of uncontrolled hypertension, one of ordinary skill in the art would have understood that treatment directed toward reducing the underlying hypertension would likewise have been expected to prevent and/or treat such hypertension-related disorders. Accordingly, it would have been obvious to utilize the SNAT2 competitive inhibitor discussed above for preventing and/or treating hypertension and relevant disorders.
Claim 14 is included in this rejection because claim 14 depends from claim 11 and does not eliminate the alternative embodiments recited therein. The present rejection relies upon the embodiment reciting use of a SNAT2 competitive inhibitor or a substance having SNAT2 competitive inhibitory activity. The additional wherein clause of claim 14 further limits only the separate alternative embodiment directed to substances having SNAT2 gene and/or gene product inhibitory activity and therefore does not exclude the competitive inhibitor embodiment relied upon in the present rejection.
Conclusion
No claim is in condition for allowance.
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/NAGHMEH NINA MOAZZAMI/Examiner, Art Unit 1652
/ROBERT B MONDESI/Supervisory Patent Examiner, Art Unit 1652
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