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 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.
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 .
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on March 23, 2026.
Claims 1-4 and 9-13 are pending and are examined in accordance to the elected species. Claims 5-8 are canceled.
Action Summary
The objection to claims 4, 12, and 13 has been withdrawn in light of the claim amendment.
Claims 9 and 10 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are withdrawn in light of the claim amendment.
Claim 4 and 11 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form, are withdrawn in light of the claim amendment.
Claims 1-4 and 9-13 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as been not enabled for prevention, are withdrawn in light of the claim amendment.
Claims 1-4 and 9-13 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.
Claims 1-4 and 9-13 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.
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.
Claims 1-4 and 9-13 remain 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).
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].) 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.) Guangxin also teaches the malate crystal form is in a unit dose of 100 mg. (See paragraph [0125].) Guangxin further contemplates formulation in the form of a tablet, a capsule, or intravenous injection. (See paragraph [0077].)
Guangxin does teach chronic renal insufficiency (chronic kidney disease) with chronic heart failure (congestive heart failure). chronic renal insufficiency with chronic heart failure is a form of cardiorenal syndrome.
Schroten teaches Directly blocking the active site of renin may provide important information. It was already in 1980 that the first studies were performed with a renin inhibitor; however, the effectiveness of this renin inhibitor was poor, mainly due to lack of specificity. Recently, an orally active renin inhibitor, aliskiren, has become commercially available, and several other direct renin inhibitors are in development. Numerous studies are now trying to establish the potentials for this treatment in CV and renal disease. Despite low bioavailability, aliskiren blocks the active site of renin and effectively lowers PRA, thus providing very useful information on the role of PRA outside the classical RAAS pathway. (See last paragraph of the right column of page 196 bridging first paragraph of the left column of page 197.) Moreover, Shroten teaches there is also some evidence that direct renin inhibition may improve renal function in patients with heart failure by improving effective renal plasma flow (ERPF). (See second paragraph of the right column of page 197.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to use the method of Guangxin for treating chronic kidney insufficiency with chronic heart failure to give Applicant’s claimed method. One would have been motivated to do so, because not only Guangxin teaches morpholine derivative malate salt crystal form as a renin inhibitor can be used for treating hypertension, cardiac insufficiency, diabetic nephropathy, but also because Shroten teaches renin inhibitor such as aliskiren is known to be effective for improving renal function in patients with heart failure. One would reasonably expect the crystal malate salt of the morpholine derivative compound of Guangxin which as great water solubility and improved stability (See Abstract of Guangxi) as a renin inhibitor to effectively treat chronic kidney insufficiency with chronic heart failure with success as this compound would perform better than alkiskiren due to its great properties.
Acknowledgement is made of the receipt and entry of Applicant’s remarks/arguments filed on December 09, 2024.
Applicant’s argument
Applicant argues that Guangxin does not teach chronic insufficiency with CHF.
Examiner’s response
In response, Applicant’s argument is not persuasive. Guangxin expressly teaches the use of the claimed morpholine derivative malate salt as renin inhibitor for treating cardiac insufficiency and renal-related disease, including diabetic nephropathy. These disclosures demonstrate that the compound is useful in both cardiac and renal dysfunction contexts. Schroten further teaches that direct renin inhibition improves renal function in patient with heart failure, including by improving effective renal plasma flow. Thus, the applied prior art establishes a recognized pathological relationship between heart failure and renal impairment mediated by renin-angiotensin-aldosterone system (RAAS). Accordingly, the claimed indication-chronic renal insufficiency with chronic heart failure-represents no more than the predictable use of a known renin inhibitor in a patient population in which cardiac and renal dysfunction coexists, as taught by the combined references.
Applicant’s argument
Applicant argues that diabetic nephropathy is a completely different disease.
Examiner’s response
In response, Applicant’s argument is not persuasive because it improperly focuses on disease nomenclature rather than underlying mechanism. Specifically, Guangxin teaches renal dysfunction (e.g., diabetic nephropathy) using a renin inhibitor. Schroten teaches that renin inhibition improves renal function in heart failure patients, demonstrating that renin-mediated pathways are common to multiple forms of renal impairment. One of ordinary skill in the art would have understood that renal insufficiency, regardless of etiology, involves overlapping RASS-mediated mechanism, and therefore, would have expected that a known renin inhibitor effective in renal disease would also be effective in renal insufficiency associated with heart failure. Thus, the claimed disease state is not distinct in a way that would preclude a reasonable expectation of success, but rather represents a predictable application within the same mechanistic pathway.
Applicant’s argument
Applicant argues that Schroten does not disclose the claimed compound.
Examiner’s response
In response to applicant's arguments against the references individually, one cannot show nonobviousness 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). Schroten is not relied upon to disclose the claimed compound, but rather to demonstrate that renin inhibiton is effective for improving renal function in heart failure patients. Guangxin provides the claimed compoiund and teaches its use as renin inhibitor. The combination therefore, properly relies on Guangxin’s compound plus salt plus crystal and plus therapeutic class and Schroten gives the motivation and expectation of success in HF and renal context. Such use of secondary reference is proper under KSR.
Applicant’s argument
Applicant argues that there is not reasonable expectation of success.
Examiner’s response
In response, Applicant’s argument is not persuasive. Specifically, Schroten provides evidence that renin inhibition improves renal function in patients with heart failure, thereby directly supporting a reasonably expectation of success that a known inhibitor (as taught by Guangxin) would be effective in treating renal insufficiency in heart failure patients. Where the prior art provides both a known compound with established mechanism, and clinical or mechanistic evidence supporting that mechanism in the claimed disease context, a reasonable expectation of success is established.
Applicant’s argument
Applicant argues that Example 1 of the present application shows after 8 weeks of administration of the malate salt of the claimed compound at 1-5 mg/kg once daily orally, a lowering of blood pressure was observed with no risk of hyperkalemia at the same time.
Examiner’s response
In response, Applicant’s argument is not persuasive. Applicant’s experimental data are not commensurate in scope with the claims and therefore do not outweigh the strong prima facie case of obviousness. The claims broadly encompass any administration route any pharmaceutically acceptable salt thereof, any subject, and any dose, whereas the evidence is limited to a specific malate salt, a specific dose regimen, and animal model. Moreover, the reported improvements in proteinuria and eGFR are consistent with the known effect of renin inhibition on renal function, as evidenced by Schroten, and therefore, do not constitute unexpected results sufficient to overcome the rejection.
Accordingly, the claimed method represents no more than the predictable use of a known renin inhibitor for treating a closely related and mechanistically linked disease state, and the rejection 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 1-4 and 9-13 remain 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 U.S. 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 U.S, patent claims do not teach chronic renal insufficiency (chronic kidney disease) with chronic heart failure (congestive heart failure).
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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555
898
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Greyscale
(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].) 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.) Guangxin also teaches the malate crystal form is in a unit dose of 100 mg. (See paragraph [0125].) Guangxin further contemplates formulation in the form of a tablet, a capsule, or intravenous injection. (See paragraph [0077].)
Schroten teaches directly blocking the active site of renin may provide important information. It was already in 1980 that the first studies were performed with a renin inhibitor; however, the effectiveness of this renin inhibitor was poor, mainly due to lack of specificity. Recently, an orally active renin inhibitor, aliskiren, has become commercially available, and several other direct renin inhibitors are in development. Numerous studies are now trying to establish the potentials for this treatment in CV and renal disease. Despite low bioavailability, aliskiren blocks the active site of renin and effectively lowers PRA, thus providing very useful information on the role of PRA outside the classical RAAS pathway. (See last paragraph of the right column of page 196 bridging first paragraph of the left column of page 197.) Moreover, Shroten teaches there is also some evidence that direct renin inhibition may improve renal function in patients with heart failure by improving effective renal plasma flow (ERPF). (See second paragraph of the right column of page 197.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to use the compound taught by the U.S. patent claims for treating chronic kidney insufficiency with chronic heart failure to give Applicant’s claimed method. One would have been motivated to do so, because not only Guangxin teaches morpholine derivative malate salt crystal form, which is the same compound as that of the U.S. patent claim, as a renin inhibitor can be used for treating hypertension, cardiac insufficiency, diabetic nephropathy, but also because Shroten teaches renin inhibitor such as aliskiren is known to be effective for improving renal function in patients with heart failure. One would reasonably expect the crystal malate salt of the morpholine derivative compound of the U.S. patent claims which as great water solubility and improved stability as a renin inhibitor according to Guangxi to effectively treat chronic kidney insufficiency with chronic heart failure with success as this compound would perform better than alkiskiren due to its great properties.
Applicant’s argument substantially mirrors the argument presented against the 103 rejection and is not persuasive for at least the same reason discussed above. However, Applicant’s augment is further deficient because it does not address the proper basis of the rejection-namely, whether the presently claimed inention is patentably distinct from the claims of the U.S. patent 10,519,150. As explained in the rejection, the claims of the ‘150 patent teach the same or closely related compound as renin inhibitor. Schroten provides evidence that renin inhibition improves renal function in patients with heart failure, thereby directly supporting a reasonably expectation of success that a known inhibitor (as taught by Guangxin) would be effective in treating renal insufficiency in heart failure patients. Where the prior art provides both a known compound with established mechanism, and clinical or mechanistic evidence supporting that mechanism in the claimed disease context, a reasonable expectation of success is established.
Conclusion
Claims 1-4 and 9-13 are not allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEAN P CORNET whose telephone number is (571)270-7669. The examiner can normally be reached Monday-Thursday from 7.00am-5.30pm.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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