Please vacate the Nono-final rejection m mailed August 11, 2026 is hereby vacated and superseded by the present Office Action. The prior Office Action inadvertently included a form paragraph pertaining to finality. The present Office Action corrects that inadvertent error and supersedes the prior Office Action in its entirety.
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/22/2026 has been entered.
Election/Restrictions
Applicant's election with traverse of malate salt species of the compound of the formula (I) and chronic renal insufficiency with chronic heart failure species in the reply filed on 11/19/2025 is acknowledged and maintained.
Priority
This application is a filing under 35 U.S.C. § 371 of International Application No.
PCT/CN2021/116338, filed September 09, 2021, which claims foreign priority to Chinese application number CN202010921155.4, filed September 04, 2020 .
Information Disclosure Statement
The information disclosure statement(s) previously considered by the Examiner remain of record and need not to be resubmitted.
Status of Claims
Claims 1-4 and 11-12 are pending and are examined in accordance to the elected species. Claims 5-10 and 13 are canceled.
Action Summary
Claims 1-4 and 11-12 rejected under 35 U.S.C. 103 as being unpatentable over Guangxin et al (EP3 398 946 A) in view of Schroten et al (Heart Fail Rev (2012) 17:191–201), are maintained, but modified and revisited.
Claims 1-4 and 11-12 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 10,519,150 in view of Guangxin et al (EP3 398 946 A) in view of Schroten et al (Heart Fail Rev (2012) 17:191–201), are maintained, but modified and revisited.
Claim Objections
Claim 12 is objected to as being in improper form because it depends from a canceled claim 10. A dependent claim must refer back to a preceding claim and further limit the subject matter thereof, Applicant is required to amend claim 12 to depend from an appropriate pending claim and to incorporate any lamination necessary to maintain the intended scope of the claim. See MPEP § 608.01(n). Accordingly, claims 12 will not be examined further on the merits in this Office action due to this unclear dependency.
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 non-obviousness.
Claims 1-4 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Guangxin et al. (EP3 398 946 A1; hereinafter “Guangxin”)) in view of Schroten et al. (Heart Fail Rev (2012) 17:191–201; hereinafter “Schroten”).
Guangxin teaches a morpholine derivative malate salt formed by the morpholine derivative and L-malic acid in a molar ratio of 1:1, and represented by the following structural formula:
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(See paragraph [0006].) Moreover, Guangxin teaches the morpholine derivative crystal salt as a renin inhibitor, and a use thereof in the preparation of a drug for the treatment and/or prevention of diseases such as hypertension, cardiac insufficiency, diabetic nephropathy et… (See paragraph [0079].) So Guangxin expressly establishes that the presently claimed compound is pharmaceutically active as a renin inhibitor and recognizes therapeutic utility of the compound in both cardiac and renal disease contexts. Guangxin further teaches the morpholine derivative malate is a crystal form having characteristic peaks at 2θ of 7.767° ±0.2°, 13.897° ±0.2°, 14.775° ±0.2°, 17.098° ±0.2°, 18.999° ±0.2°, 20.153o ±0.2°, 20.960° ±0.2°, 21.423° ±0.2°, 26.348° ±0.2°, 27.892° ±0.2° in the X-ray powder diffraction pattern and further has characteristic peaks at 2θ of 5.598° ±0.2°, 7.357° ±0.2°, 10.395° ±0.2°, 11.108° ±0.2°, 16.037° ±0.2°, 16.523° ±0.2°, 19.410° ±0.2°, 22.645° ±0.2°, 26.630° ±0.2°, 26.891° ±0.2°, 27.380° ±0.2°, 31.056° ±0.2°, 33.306° ±0.2°, 33.775° ±0.2°, 39.231° ±0.2° in the X-ray powder diffraction pattern as recited in claim 11. (See claims 2 and 3.) Guangxin additionally contemplates administration of the malate crystal form in pharmaceutical dosage forms, including, inter alia, a tablet, a capsule, or intravenous injection. (See paragraph [0077].) Guangxin further teaches a 100 mg unit dose of the malate crystalline form. (See paragraph [0125].) Accordingly, Guangxin expressly teaches at least one of the alternatively recited unit-dose amounts of amended claim 1. The disclosed 100 mg amount also falls within the 25 mg to 200 mg range in claim 12.
Guangxin does expressly teach administering the compound of Formula I for the particular indication recited in claim 1, namely, treating chronic renal insufficiency (chronic kidney disease) with chronic heart failure.
Schroten discusses direct inhibition of renin in the context of cardiovascular and renal disease. Shroten teaches that orally active renin inhibitor, aliskiren, blocks the active site of renin and effectively lowers plasma renin activity and explains that studies were investigating the therapeutic potential of direct renin inhibitor in cardiovascular and renal disease. (See second paragraph of the right column of page 197.) Significantly, Schroten further teaches that there is evidence that direct renin inhibition may improve renal function in patient with heart failure by improving effective plasma flow (ERPF). (See page 197.) Thus, Schroten is not relied upon to disclose the compound of Formula I, its salt or crystalline form. Nor Schroten relied upon merely for the general proposition that renal and cardiac diseases may coexist. Rather, Schroten is relied upon for its specific teaching that direct inhibition of the same pharmacological target inhibited by Guangxin’s compound-renin-may improve renal function specifically in patients with heart failure.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer the renin inhibitor taught by Guangxin to a patient having chronic renal insufficient associated with chronic heart failure, as suggested by Schroten.
One of ordinary skill in the art would have been motivated to do so because Guangxin identifies the presently compound as a renin inhibitor having recognized therapeutic utility in both cardiac insufficient and renal disease, while Schroten teaches that direct inhibition may improve renal function specifically in patients having heart failure, including by improving effective renal plasma flow.
Accordingly, the combined teachings would have provided a person of ordinary skill in the art a reason to use Guangxin’s known renin inhibitor in a patient having renal insufficient associated with chronic heart failure in order to obtain the renal therapeutic benefit associated in the art with direct inhibition in heart-failure patients.
The proposed combination does not require modification of the structure, salt form, crystalline form, dosage form, or pharmacological mechanism of Guangxin’s compound. Rather, it involves administering Guangxin’s known renin inhibitor according to its established pharmacological activity in a patient population for which Schroten specifically teaches that inhibition may provide a renal therapeutic benefit.
One of ordinary skill in the art would also have had a reasonable expectation of success in obtaining renal therapeutic benefit by administering Guangxin’s renin inhibitor to a patient having chronic renal insufficiency associated with chronic heart failure. Guangxin establishes that the presently claimed compound possesses the relevant pharmacological activity-renin inhibition- and expressly identifies therapeutic applications of the compound in both cardiac insufficiency and renal disease. Schroten independently provides evidence linking that same pharmacological mechanism to improvement of renal function specifically in patients having heart failure. Accordingly, the prior art did not merely identify renin inhibition as theoretical target. Rather, the art provided (1) the presently claimed compound and its established renin-inhibitory activity; (2) recognized cardiac and renal therapeutic uses for that compound; and (3) evidence that direct renin inhibition may improve renal function in patients having heart failure.
A reasonably expectation of success does not require certainty or absolute predictability. In view of the foregoing teachings, one of ordinary skill in the art would reasonably have expected administration of Guangxin’s known renin inhibitor to provide renal therapeutic benefit in a patient having chronic renal insufficiency associated with chronic heart failure.
Accordingly, the subject matter of claims 1-4 and 11 would have been obvious over the combined teachings of Guangxin and Schroten.
Response to Applicant’s arguments
Applicant’s argument filed with the Request of continued Examination have been fully considered but not persuasive.
Applicant argues that Guangxin does not disclose chronic renal insufficiency with chronic heart failure.
Applicant specifically argues that Guangxin does not recite the words “renal” or “kidney” and does not disclose treatment of chronic renal insufficiency with chronic heart failure. Applicant further contends that the claimed comorbid disease state is completely different from the diseases disclosed by Guangxin.
In response to applicant's arguments against the references individually, one cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the present case, the examiner acknowledges that Guangxin does not expressly disclose the particular indication of treating chronic renal insufficiency with chronic heart failure. For this reason, the rejection relies upon Schroten in combination with Guangxin. Guangxin expressly teaches the claimed recited compound as a renin inhibitor and teaches its use for cardiac insufficiency and diabetic nephropathic. Schroten supplies the pertinent additional teaching that direct renin inhibition may improve renal function in patients having heart failure including improving effective renal plasma flow. The rejection therefore does not depend upon treating diabetic nephropathy as identical to chronic renal insufficiency associated with chronic heart failure. Rather, Guangxin establishes the identity and pharmacological activity of the claimed compound, whereas Schroten provides the specific therapeutic connection between direct renin inhibition and improvement of renal function in the heart-failure patient population.
Applicant argues that cardiorenal disease is complex and therefore unpredictable.
Applicant argues that chronic renal insufficiency with chronic heart failure is not a simple superposition of two individual disease and identifies a bidirectional relationship between the heart and kidney involving hemodynamic alterations and neurohormonal activation.
In response, Applicant’s argument is not persuasive. The rejection does not rest upon the proposition that the effects observed in an isolated cardiac disorder and an isolated renal disorder can simply be added together to predict treatment of the claimed comorbidity. Instead, Schroten specifically addresses the intersection relied upon by the Examiner: renal function in patient already having heart failure. Moreover, Applicant’s own discussion recognizes neurohormonal activation particularly activation of the renin-angiotensin-aldosterone system (RAAS), as part of the pathological interaction between renal insufficiency and heart failure. Thus, the complexity identified by Applicant does not eliminate the therapeutic relevance of the renin pathway relied upon by the applied references. The issue is not whether therapeutic success was guaranteed, but whether the prior art provided a reason to make the claimed therapeutic application with a reasonable expectation of success. Schroten’s express teaching concerning improvement of renal function through direct renin inhibition in heart-failure patients provides such a reason.
Applicant argues that aliskiren is structurally different from Formula I
Applicant argues that aliskiren has a chemical structure significantly different from the compound of Formula I.
In response, this argument is not persuasive because Schroten is not relied upon to provide the claimed compound or to suggest structurally modifying aliskiren to arrive at Formula I. Guangxi expressly provides the compound of Formula I and identifies that compound as a renin inhibitor. Schroten is relied upon for a different teaching: the therapeutic relevance of direct renin inhibition to renal function in patients with heart failure. Accordingly, the rejection does not require a person of ordinary skill in the art to select aliskiren as a lead compound or modify aliskiren into the presently claimed compound. The structurally difference between aliskiren and Formula I therefore do not address the actual rationale underlying the combination.
Applicant’s reliance on Gheorghiade et al. (2013), submitted in the IDS filed on 07/22/2026, and argues that the ASTRONAUT trial demonstrates that aliskiren did not significantly improve cardiovascular mortality or heart-failure readmission and increased the incidence of hyperkalemia, hypotension, and renal impairment.
The evidence has been fully considered, but does not negate the prima facie case.
First, ASTRONAUT did not evaluate aliskiren as monotherapy. Rather, the trial evaluated the addition of aliskiren to standard therapy in patients hospitalized for worsening heart failure. As reflected in the study, the great majority of patents were already receiving other therapies affecting the RAAS, including ACE inhibitor or angiotensin receptor blockers, and many additionally received mineralocorticoid receptor antagonists. Thus, although ASTRONAUT associates addition of aliskiren with increased renal impairment, hyperkalemia, and hypotension relative to placebo on background standard therapy, the study does not establish that such findings would result from direct renin inhibition as monotherapy, as opposed to additional renin inhibition superimposed upon the existing therapeutic regimen or the combined pharmacological effects thereof. This distinction was expressly recognized in the art following ASTRONAUT. Esteras et al. (Ther Adv Drug Saf. 2015 Aug;6(4):166–176) cited to solely to rebut Applicant’s argument regarding ASTRONAUT, explains that regulatory concerns were directed to dual RAS blockage involving combined used of ACE inhibtors, ARS, or aliskiren and reports increased risks of hyperkalemia, hypotension, and renal failure associated with such combination therapy. (See right col.; page 167.) Esteras further explains that clinical evidence associated with dual RAS blockade with increased hypotension, hyperkalemia, and renal failure compared with monotherapy. (See left col.; page 166.) The regulatory distinction is particularly instructive. Esteras reports that use of aliskiren with either an ARB or ACE inhibitor was contraindicated in patient with diabetes mellitus and chronic kidney disease stage 3-5. (See Box 1 of left col.; page 166.) Indeed, Esteras expressly recognizes RAS-targeting monotherapy as a therapeutically valuable intervention and states that such intervention delay CKD progression, while separately identifying benefits of RAS-targeting therapy in chronic heart failure. (See left col.; page 171)
The presently claimed method does not require administering Formula I together with an ACE inhibitor, ARB, or other RAS-blocking agent. Thus, the dual-blockage safely concerns relied upon by Applicant do not establish that the presently claimed administration of Guangxin’s renin inhibitor would have lacked a reasonable expectation of renal therapeutic benefit.
Second ASTRONAUT was not designed to determine whether Formula I, or even direct renin inhibitor monotherapy, treats chronic renal insufficiency. Its principal efficacy endpoint concerned cardiovascular death and heart-failure rehospitalization. Failure of adjunctive aliskiren to significantly improve those cardiovascular endpoints does not establish lack of renal therapeutic activity for the presently claimed compound.
Third, ASTRONAUT evidence does not establish that the art taught away from direct renin inhibition generally. Rather, it establishes limitations and safety concerns associated with the particular adjunctive therapeutic regimen studies. Esteras confirms that the recognized regulatory concern involved combination or dual RAS blockage and that the art continued to distinguish monotherapy from dual blockade.
Accordingly, Gheoghiade does not negate Schroten’s specific teaching that direct renin inhibition may improve renal function in patients having heart failure.
Applicant argues that the references do not teach the amended dosage-form/unit-dose limitations.
Applicant’s argument regarding the newly added limitation of claim 1 has also been considered, but is not persuasive.
Guangxin expressly teaches pharmaceutical dosage forms including tablets, capsules, and intravenous injection. (See paragraph [077].) Claim 1 recites the various dosage forms in the alternative; therefore, disclosure of any one of the recited alternatives satisfies this limitation. Guangxin further teaches a 100 mg unit dose. (See paragraph [0125].) Claim 1 recites 25 mg, 50 mg, 100 mg, 150 mg, or 200 mg in the alternative. Guangxin therefore, expressly teaches one of the claimed unit-dose amounts. Accordingly, the newly added dosage-from and unit-dose limitations do not distinguish claim 1 from the combined teachings of Guangxin and Schroten.
Applicant argues that neither reference teaches the entire claimed method
To the extend Applicant argues that neither Guangxin and Schroten individually discloses every limitation of claim 1, the argument does not address the rejection as made. The rejection is based upon the combined teachings of the references. Guangxin provides the claimed compound, renin-inhibitory activity, salt/crystalline forms, pharmaceutical dosage forms, unit dose, and cardiac/renal therapeutic context. Schroten provides the teaching that direct renin inhibition may improve renal function in patients with heart failure. The obviousness inquiry is what the combined teachings would have suggested to one of ordinary skill in the art, rather than whether either reference individually anticipates or render obvious the claimed invention. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues that there was not reasonable expectation of success
Applicant’s argument that a person of ordinary skill would not have reasonably expected the claimed treatment to success is likewise not persuasive. As discussed above, Guangxin establishes that the claimed compound is an active renin inhibitor having recognized therapeutic applications in cardiac and renal disorders. Schroten provides the additional, specific teaching that direct renin inhibition may improve renal function in patients with heart failure. Applicant’s own ASTROANUT evidence does not establish that direct renin inhibitor monotherapy would have been expected to fail. Instead, the negative findings relied upon by Applicant arose from addition of aliskiren to standard HF therapy, including substantial background Ras blockade. Esteras subsequently characterized the relevant safety concerns as associated with dual RAS blockade compared to monotherapy, rather than establishing therapeutic futility of RAS inhibition itself. Obviousness requires a reasonable expectation of success, not certainty that that the treatment will success in every patient or absence of any potential adverse effect. Considering the evidence as a whole, the teaching of Guangxin and Schroten would have provided a person of ordinary skill with both a reason to administer Guangxin’s renin inhibitor in the claimed cardiorenal setting with a reasonable expectation of success of obtaining renal therapeutic.
Applicant’s experimental results
To the extent Applicant continues to rely upon the experimental results of the present application, including reported effects on blood pressure, proteinuria, eGFR, and/or hyperkalemia, the evidence has been considered. However, the evidence must me reasonably commensurate in scope with the claims and must demonstrate a result that would have been unexpected relative the closest prior art. Claim 1 broadly encompasses Formula I or a pharmaceutically acceptable salt thereof, multiple alternatively recited dosage forms, and multiple unit-dose amounts. To the extent Applicant relies upon results obtained with a particular malate salt, particular dose or dosing regimen, and particular experimental model, such evidence is narrower that the scope of claim 1. Furthermore, improvements in renal-related parameters must be considered against Schroten’s teaching that direct renin inhibition may improve renal function in patients with heart failure. Thus, renal improvement is attributable to renin inhibition is not, standing alone, an unexpected result sufficient to overcome the prima facie case. To the extent Applicant contends that absence or reduction of hyperkalemia constitutes an unexpected result, claim 1 does not require absence of hyperkalemia, a particular potassium concentration, or any defined safety outcome. Moreover, the ASTRONAUT combination-therapy data do not establish the expected safety profile of the presently claimed compound when administered outside a dual-RAS-blockade regimen.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4 and 11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 10,519,150 in view of Guangxin et al (EP3 398 946 A) in view of Schroten et al (Heart Fail Rev (2012) 17:191–201).
The patent claims teach teaches a morpholine derivative malate salt formed by the morpholine derivative and L-malic acid in a molar ratio of 1:1, and represented by the following structural formula:
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(See paragraph [0006].) Moreover, Guangxin teaches the morpholine derivative crystal salt as a renin inhibitor. (See claim 1.) The morpholine derivative malate is a crystal form having characteristic peaks at 2θ of 7.767° ±0.2°, 13.897° ±0.2°, 14.775° ±0.2°, 17.098° ±0.2°, 18.999° ±0.2°, 20.153o ±0.2°, 20.960° ±0.2°, 21.423° ±0.2°, 26.348° ±0.2°, 27.892° ±0.2° in the X-ray powder diffraction pattern. The morpholine derivative malate crystal form further has characteristic peaks at 2θ of 5.598° ±0.2°, 7.357° ±0.2°, 10.395° ±0.2°, 11.108° ±0.2°, 16.037° ±0.2°, 16.523° ±0.2°, 19.410° ±0.2°, 22.645° ±0.2°, 26.630° ±0.2°, 26.891° ±0.2°, 27.380° ±0.2°, 31.056° ±0.2°, 33.306° ±0.2°, 33.775° ±0.2°, 39.231° ±0.2° in the X-ray powder diffraction pattern. (See claims 2 and 3.)
The patent claims do not expressly teach administration of the Formula I for treating chronic renal insufficiency in patients having chronic heart failure. The patent claims do not expressly teach the compound is administered in a dosage form and a unit dose recited in claim 1.
Guangxin teaches a morpholine derivative malate salt formed by the morpholine derivative and L-malic acid in a molar ratio of 1:1, and represented by the following structural formula:
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(See paragraph [0006].) Moreover, Guangxin teaches the morpholine derivative crystal salt as a renin inhibitor, and a use thereof in the preparation of a drug for the treatment and/or prevention of diseases such as hypertension, cardiac insufficiency, diabetic nephropathy et… (See paragraph [0079].) So Guangxin expressly establishes that the presently claimed compound is pharmaceutically active as a renin inhibitor and recognizes therapeutic utility of the compound in both cardiac and renal disease contexts. Guangxin further teaches the morpholine derivative malate is a crystal form having characteristic peaks at 2θ of 7.767° ±0.2°, 13.897° ±0.2°, 14.775° ±0.2°, 17.098° ±0.2°, 18.999° ±0.2°, 20.153o ±0.2°, 20.960° ±0.2°, 21.423° ±0.2°, 26.348° ±0.2°, 27.892° ±0.2° in the X-ray powder diffraction pattern and further has characteristic peaks at 2θ of 5.598° ±0.2°, 7.357° ±0.2°, 10.395° ±0.2°, 11.108° ±0.2°, 16.037° ±0.2°, 16.523° ±0.2°, 19.410° ±0.2°, 22.645° ±0.2°, 26.630° ±0.2°, 26.891° ±0.2°, 27.380° ±0.2°, 31.056° ±0.2°, 33.306° ±0.2°, 33.775° ±0.2°, 39.231° ±0.2° in the X-ray powder diffraction pattern as recited in claim 11. (See claims 2 and 3.) Guangxin additionally contemplates administration of the malate crystal form in pharmaceutical dosage forms, including, inter alia, a tablet, a capsule, or intravenous injection. (See paragraph [0077].) Guangxin further teaches a 100 mg unit dose of the malate crystalline form. (See paragraph [0125].) Accordingly, Guangxin expressly teaches at least one of the alternatively recited unit-dose amounts of amended claim 1. The disclosed 100 mg amount also falls within the 25 mg to 200 mg range in claim 12.
Guangxin does expressly teach administering the compound of Formula I for the particular indication recited in claim 1, namely, treating chronic renal insufficiency (chronic kidney disease) with chronic heart failure.
Schroten discusses direct inhibition of renin in the context of cardiovascular and renal disease. Shroten teaches that orally active renin inhibitor, aliskiren, blocks the active site of renin and effectively lowers plasma renin activity and explains that studies were investigating the therapeutic potential of direct renin inhibitor in cardiovascular and renal disease. (See second paragraph of the right column of page 197.) Significantly, Schroten further teaches that there is evidence that direct renin inhibition may improve renal function in patient with heart failure by improving effective plasma flow (ERPF). (See page 197.) Thus, Schroten is not relied upon to disclose the compound of Formula I, its salt or crystalline form. Nor Schroten relied upon merely for the general proposition that renal and cardiac diseases may coexist. Rather, Schroten is relied upon for its specific teaching that direct inhibition of the same pharmacological target inhibited by Guangxin’s compound-renin-may improve renal function specifically in patients with heart failure.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer the renin inhibitor taught by the patent claim and Guangxin to a patient having chronic renal insufficient associated with chronic heart failure, as suggested by Schroten.
One of ordinary skill in the art would have been motivated to do so because the patent claim compound is the same compound taught by Guangxin and Guangxin identifies the presently compound as a renin inhibitor having recognized therapeutic utility in both cardiac insufficient and renal disease, while Schroten teaches that direct inhibition may improve renal function specifically in patients having heart failure, including by improving effective renal plasma flow.
Accordingly, the combined teachings would have provided a person of ordinary skill in the art a reason to use the patent claims and Guangxin’s known renin inhibitor in a patient having renal insufficient associated with chronic heart failure in order to obtain the renal therapeutic benefit associated in the art with direct inhibition in heart-failure patients.
The proposed combination does not require modification of the structure, salt form, crystalline form, dosage form, or pharmacological mechanism of the patent claim and Guangxin’s compound. Rather, it involves administering the patent claims and Guangxin’s known renin inhibitor according to its established pharmacological activity in a patient population for which Schroten specifically teaches that inhibition may provide a renal therapeutic benefit.
One of ordinary skill in the art would also have had a reasonable expectation of success in obtaining renal therapeutic benefit by administering the patent claims and Guangxin’s renin inhibitor to a patient having chronic renal insufficiency associated with chronic heart failure. The patent claims and Guangxin establishes that the presently claimed compound possesses the relevant pharmacological activity-renin inhibition- and Guangxin expressly identifies therapeutic applications of the compound in both cardiac insufficiency and renal disease. Schroten independently provides evidence linking that same pharmacological mechanism to improvement of renal function specifically in patients having heart failure. Accordingly, the prior art did not merely identify renin inhibition as theoretical target. Rather, the art provided (1) the presently claimed compound and its established renin-inhibitory activity; (2) recognized cardiac and renal therapeutic uses for that compound; and (3) evidence that direct renin inhibition may improve renal function in patients having heart failure.
A reasonably expectation of success does not require certainty or absolute predictability. In view of the foregoing teachings, one of ordinary skill in the art would reasonably have expected administration of the patent claims and Guangxin’s known renin inhibitor to provide renal therapeutic benefit in a patient having chronic renal insufficiency associated with chronic heart failure.
Accordingly, the subject matter of claims 1-4 and 11 is an obvious variation of the combined teachings of the patent claims, Guangxin and Schroten.
Applicant argues that the claims of U.S. Patent No. 10/519,150 are based on Guangxin and Shroten or continuations thereof, for the same reasons advanced against the 103-rejection.
Applicant’s arguments have been considered but are not persuasive. Because Applicant relies on the same substantive arguments addressed above with respect to Guangxin and Shroten or continuations thereof, the Examiner’s response thereto are incorporated herein by reference and are equally applicable to the nonstatutory double patenting rejection. Accordingly, the nonstatutory double patenting rejection is maintained.
Conclusion
Claims 1-4 and 11-12 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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