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 .
Remarks
The amendments and remarks filed on 09/05/2025 have been entered and considered. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior office action. The rejections and/or objections presented herein are the only rejections and/or objections currently outstanding. Any previously presented objections or rejections that are not presented in this Office Action are withdrawn. Claims 13-22 are pending; Claims 1-12 are cancelled; Claims 13-15 and 18 are amended; Claims 19-22 are new; and Claims 16-17 are withdrawn; and Claims 13-15 and 18-22 are under examination.
The species election requirement set forth in the prior office action dated 12/04/2024 is still maintained since the elected species, i.e. a compound/sacubitril that inhibits degradation of amyloid beta peptide, is not allowable.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/08/2025 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97 and is being considered by the examiner.
Withdrawal of Objections
The objection to Claims 13 and15 is withdrawn due to the amendment to the claims filed on 09/05/2025.
Withdrawal of Rejections
The rejection of Claims 1, 4, 6 and 13-14 under 35 U.S.C. 101 is withdrawn due to the cancellation of the claims 1, 4, and 6 as well as the amendment to the claims 13-14, which now limit the elected species (inhibitor compound) to be a chemically synthesized compound: sacubitril.
The rejection of Claims 1, 4-6, 13-15, and 18 under 35 U.S.C. 112(b) is withdrawn due to the cancellation of or amendment to the claims.
The rejection of Claims 1, 4 and 6 under 35 U.S.C. 102(a)(1) as being anticipated by Reul is withdrawn due to the cancellation of or amendment to the claims.
The rejection of Claims 1 and 4-6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Thum et al. is withdrawn due to the cancellation of or amendment to the claims.
The rejection of Claims 1, 4, 6, and 15 under 35 U.S.C. 103 as being obvious over Reul is withdrawn due to the cancellation of or amendment to the claims.
Claim Rejections - 35 USC § 112(d), or 112, Fourth Paragraph
Claim 14 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. This rejection is maintained.
The base claim 13 is directed to a composition comprising sacubitril and a pharmaceutically acceptable excipient, whereas the limitation recited in the dependent claim 14 is directed to the intended use of treating liver fibrosis/cirrhosis in the preamble of Claim 13 and it does not further limit the structure of the composition of the claim 13. Therefore, Claim 14 fails to further limit Claim 13.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent clai0m(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112, First Paragraph
Claims 13-15 and 18-22 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 treating early stages of liver cirrhosis or fibrosis and for preventing liver cirrhosis or fibrosis, does not reasonably provide enablement for treating any liver cirrhosis/fibrosis other than early stages of liver cirrhosis/fibrosis. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention the invention commensurate in the entire scope with these claims.
In making a determination as to whether an application has met the requirements for enablement under 35 U.S.C. 112 ¶ 1, the following factors enumerated In re Wands, 8 USPQ2d 1400, at 1404 (CAFC 1988) are considered: (1) the breadth of the claims, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the quantity of experimentation necessary. While it is not essential that every factor be examined in detail, those factors deemed most relevant should be considered.
The breadth of the claims. Claims 15 and 18-22 are directed to methods for treating or preventing liver cirrhosis or fibrosis, comprising a single step of administering to a subject a pharmaceutically effective amount of sacubitril (a neprilysin inhibitor for inhibiting degradation of an amyloid beta protein or amyloid peptides) or a composition there of; wherein the liver cirrhosis or fibrosis can be any stages of liver cirrhosis or fibrosis, whose scope encompasses clinically irreversible stages of liver cirrhosis. Claims 13-14 are directed to a pharmaceutical composition comprising sacubitril for use in the treatment of any stages of liver cirrhosis or fibrosis (including clinically irreversible stages of liver cirrhosis); wherein the liver cirrhosis or fibrosis can comprise primary biliary cirrhosis, nonalcoholic steatohepatitis, alcohol hepatitis, hepatocellular carcinoma, or viral hepatitis.
The amount of direction or guidance presented and the existence of working examples. In the specification there is no working example for using the neprilysin inhibitor sacubitril for treating liver cirrhosis or fibrosis in an animal. Examples in pages 14-23 of the specification only disclose multiple tests in cell lines and isolated human tissues under in vitro conditions, which demonstrated levels of amyloid beta protein or peptides are associated with liver cirrhosis. However, there is no data (in vitro or in vivo) in the specification to show administration of neprilysin inhibitor/sacubitril to a subject can treat any stages of any liver cirrhosis or fibrosis. The specification fails to provide any information regarding what specific amount of neprilysin inhibitor/sacubitril can be considered as a pharmaceutically effective amount for being used in the claimed method for treating any liver cirrhosis or fibrosis (including clinically irreversible stages of liver cirrhosis), and how to use the claimed method to reach the goal of treating any stages of any liver cirrhosis or fibrosis, such as primary biliary cirrhosis, nonalcoholic steatohepatitis, alcohol hepatitis, hepatocellular carcinoma, and viral hepatitis.
The state of prior art, and the predictability or unpredictability of the art. The art as evidenced by Reul (Dissertation, 2018, cited in IDS, described in details in 103 rejection below) teaches only early stages of liver cirrhosis can be treated by using a combination of a neprilysin inhibitor and an angiotensin II type 1 receptor blocker. There is no teaching or suggestion in the prior art indicating that any other stages of liver cirrhosis can be treated in a subject by administering a neprilysin inhibitor/sacubitril, especially for treating clinically irreversible stages of liver cirrhosis. Furthermore, Zhang et al. (Medicine, 2023, 102:32, pages 1-3, of record) reports that a combination of sacubitril/valsartan induced a serious liver injury in a subject not having any previous history of liver diseases (see title, abstract, page 1/col 2). This report indicates the outcome of administering the neprilysin inhibitor/sacubitril could lack predictability.
The quantity of experimentation necessary. It is not routine in the art to use the neprilysin inhibitor/sacubitril for treating liver cirrhosis/fibrosis other than early stages of liver cirrhosis/fibrosis in an animal subject. Neither the prior art nor disclosure of the specification shows that any liver cirrhosis other than early stages of liver cirrhosis (such as later stage of primary biliary cirrhosis and hepatocellular carcinoma) could be treated by administering the claimed sacubitril compound or composition. Therefore, in absence of any guidance, one of skill in the art would have to carry out a large amount of experimentation to find which additional steps or additional compounds need to be included in the disclosed method, or how to modify the disclosed method, to reach the goal of treating any liver cirrhosis/fibrosis other than early stages of liver cirrhosis.
Therefore, the full scope of Claims 13-15 and 18-22 are not enabled due to the lack of information and guidance with regard to how to use the neprilysin inhibitor sacubitril for treating any liver cirrhosis or fibrosis other than early stages of liver cirrhosis/fibrosis in an animal subject. Neither the specification nor the prior art enable the entire scope of the claimed invention.
Claims 15 and 18-22 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(s), at the time the application was filed, had possession of the claimed invention.
Claims 15 and 18-22 are directed to methods for preventing or treating any stages of liver cirrhosis or fibrosis, comprising a step of administering to a subject a pharmaceutically effective amount of a neprilysin inhibitor/sacubitril or a pharmaceutical composition thereof for preventing or treating any stages of liver cirrhosis or fibrosis, which encompasses clinically irreversible stages of liver cirrhosis. Support for the limitation “a pharmaceutically effective amount” recited in claims 15, 18, 19, and 21 is not found in the instant specification. The disclosure does not describe at what specific amount ranges the compound or pharmaceutical composition of sacubitril is effective at preventing or treating any stages of liver cirrhosis or fibrosis, especially clinically irreversible stages of liver cirrhosis. There is no description or working example in the specification for written description support regarding how a specific effective amount of sacubitril or a composition thereof can be determinized and used for effectively treating any stages of liver cirrhosis or fibrosis (including final and clinically irreversible stages of liver cirrhosis).
In order for the written description provision of 35 USC 112, first paragraph to be satisfied, Applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed. For example, MPEP 2163 states in part,
An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that “without such disclosure, the claimed methods cannot be said to have been described.”)
.
The liver cirrhosis or fibrosis prevented or treated by administering sacubitril in the claimed methods encompass various cirrhosis or fibrosis with distinct pathogenic mechanisms and various severe stages (such as clinically irreversible stages of cirrhosis diseases). It is not routine in the art to use the neprilysin inhibitor sacubitril for treating any later stages of liver cirrhosis/fibrosis in an animal subject. Without additional information, the skilled artisan cannot envision which specific pharmaceutically effective amounts can be applied to subjects for treating later stages of various kinds of liver cirrhosis or fibrosis (including final and clinically irreversible stages of liver cirrhosis). Adequate written description requires more than a mere statement that it is part of the invention.
Therefore, the full breadth of “a pharmaceutically effective amount” of the sacubitril compound or composition thereof encompassed by the claims do not meet the written description provision of 35 USC 112, first paragraph.
Claim Rejections - 35 USC § 103
Claims 13 and 14 are rejected under 35 U.S.C. 103 as being obvious over Thum et al. (US 2021/0180054, 2021, effective filing date: 2017/12/15, of record). This rejection is maintained.
Thum et al. teach an example of medicament suitable for the prevention or treatment of cardiac disorders, specifically, a neprilysin-inhibitor, or a combination of a neprilysin-inhibitor/sacubitril and an angiotensin-II-receptor blocker/valsartan (para 0045). It is noted that the limitations for the treatment of liver fibrosus or cirrhosis in the preamble of claim 13 as well as in claim 14 are directed to the intended use of the claimed composition, and they do not limit the structure of the claimed composition. Thus, the teachings of Thum et al. meet the claimed limitations.
The specific embodiment of Thum et al. is silent about a pharmaceutically acceptable excipient in the medicament. However, it would have been obvious to add a pharmaceutically acceptable excipient to the medicament comprising the neprilysin-inhibitor sacubitril taught by Thum et al. for treating patients, because it is a common practice in the art to include a pharmaceutically acceptable excipient/carrier in a pharmaceutical composition, as supported by Thum et al., who further teach that the active compound/agent is administered to patients as a pharmaceutical composition comprising a pharmaceutically acceptable carrier (i.e. excipient) (paras 0039, 0015).
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.
Claims 13-15 and 18-22 are rejected under 35 U.S.C. 103 as being obvious over Reul (Dissertation, Rhenish Friedrich Wilhelm University of Bonn, 2018, cited in IDS) in view of Thum et al. (US 2021/0180054, 2021, effective filing date: 2017/12/15, of record). This rejection is maintained for claims 13-15 and 18, and applied to new claims 19-22.
Reul expressively teach using a neprilysin inhibitor (in combination with an angiotensin II type 1 receptor blocker) for the treatment of early stages of liver cirrhosis (abstract, last para). Reul also teach examining the influence of neprilysin in development of liver cirrhosis by comparing a group of neprilysin-deficient animals to a group of wild-type animals, wherein both groups of animals were sub-divided into: an untreated control group (non-liver cirrhosis group), and a group in which liver cirrhosis was induced (abstract, para 1) (Note: neprilysin is an enzyme that degrades amyloid beta protein, as evidenced by the disclosure of the specification, see para 0030). Reul also teaches that compared to the wild-type animals, the animals deficient in neprilysin have less fibrosis of liver tissue, which is related to effect of neuropeptide Y, a key player between the two axes; and in the absence of neprilysin higher levels of neuropeptide Y inhibit fibrosis; and neprilysin controls the key player neuropeptide Y by cleaving this peptide (abstract, para 2).
Furthermore, Reul expressively teach using an neprilysin inhibitor, combined with an angiotensin II type 1 receptor blocker, as a therapy agent (i.e. a pharmaceutical composition) for treatment of early stages of liver cirrhosis (abstract, last para), and this combination of neprilysin inhibitors and angiotensin II type 1 receptor blockers is already routinely used in the art for clinical practice for heart treatment (abstract, last para). As such, it would have been obvious to one of ordinary skill in the art to administer a pharmaceutically effective amount of a neprilysin inhibitor combined with an angiotensin II type 1 receptor blocker to a subject having early stages of liver cirrhosis for treating the liver cirrhosis, as taught by Reul.
It is noted that the neprilysin inhibitor taught by Reul is a compound which inhibits the degradation of amyloid beta protein, since neprilysin is an enzyme for degrading the amyloid beta protein, as indicated above.
The method taught by Reul differs from the method of the claims 15, 18, 19, and 21 in that the abstract of Reul is silent about using sacubitril as the neprilysin inhibitor in the therapy agent for treating patients, and is silent about including a pharmaceutically acceptable excipient in the therapy agent.
The teachings of Thum et al. are described above.
It would have been obvious to one of ordinary skill in the art to use sacubitril as the neprilysin inhibitor to combine with the angiotensin II receptor blocker/valsartan for administering to a patient in the method of Reul for treating early stages of liver cirrhosis, because sacubitril is a neprilysin inhibitor commonly used in the prior art to be combined with the angiotensin II receptor blocker/valsartan for clinal application, as supported by Thum et al. described above.
It would have been obvious to add a pharmaceutically acceptable excipient to the pharmaceutical composition and administer the resulting pharmaceutical composition to the patient in the method suggested by Reul and Thum et al. for treating early stages of liver cirrhosis, because it is a common practice in the art to include a pharmaceutically acceptable excipient in a pharmaceutical composition, as supported by Thum et al., who further teach that medically active compound/agent is administered to patients as a pharmaceutical composition comprising a pharmaceutically acceptable carrier (i.e. excipient) (paras 0039, 0015).
Regarding the claims 13 and 14, the pharmaceutical composition used in the method suggested by Reul and Thum et al. meets all the structural limitations of the claimed composition. It is noted that the limitations for the liver fibrosus or cirrhosis in claim 14 are directed to the intended use in the preamble of claim 13 and they do not limit the structure of the claimed composition. Thus, the cited prior art renders the claims 13 and 14 to be obvious.
Regarding the claims 20 and 22, Reul and Thum et al. suggest a method of administering a pharmaceutical composition comprising sacubitril combined with angiotensin II receptor blocker/valsartan for treating early stages of liver cirrhosis. It would have been obvious to administer the pharmaceutical composition comprising sacubitril and valsartan of Reul and Thum et al. to patients having early stages of liver cirrhosis associated with or caused by liver diseases such as primary biliary cirrhosis, nonalcoholic steatohepatitis, alcohol hepatitis, hepatocellular carcinoma, and viral hepatitis recited in the claims, because any early stages of liver cirrhosis can be treated by the pharmaceutical composition comprising sacubitril in the method suggested by Reul and Thum et al. Thus, the combined teachings of the cited prior art render the claims obvious.
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.
Response to Arguments
Applicant's arguments about the claim objection in the response filed on 09/05/2025 (page 4) have been fully considered but they are moot because the objection has been withdrawn as indicated above.
Applicant's arguments about the rejection of Claims 1, 4, 6 and 13-14 under 35 U.S.C. 101 in the 09/05/2025 response (pages 4-5) have been fully considered but they are moot because the rejection has been withdrawn for the reason indicated above.
Applicant's arguments about the rejection of Claims 1, 4-6, 13-15, and 18 under 35 U.S.C. 112(b) in the 09/05/2025 response (page 5) have been fully considered but they are moot because the rejection has been withdrawn as indicated above.
Applicant's arguments about the rejection of Claim 14 under 35 U.S.C. 112(d) in the 09/05/2025 response (page 5) have been fully considered but they are not persuasive because the amended claim 14 still fails to further limit the claim 13 for the reasons indicated above.
Applicant's arguments about the rejection of Claims 1, 4 and 6 under 35 U.S.C. 102(a)(1) as being anticipated by Reul in the 09/05/2025 response (page 9) have been fully considered but they are moot because the rejection has been withdrawn as indicated above.
Applicant's arguments about the rejection of Claims 1 and 4-6 under 35 U.S.C. 102(a)(1) as being anticipated by Thum et al. in the 09/05/2025 response (page 10) have been fully considered but they are moot because the rejection has been withdrawn as indicated above.
Applicant's arguments about the rejection of Claims 13-15 and 18 under 35 U.S.C. 112(a) for lacking enablement in the entire scope of the claimed invention in the 09/05/2025 response (pages 5-8) have been fully considered but they are not persuasive for the following reasons.
In response to Applicant’s arguments in page 6/paras 2-4 of the response, the newly submitted amendment to the claims is not sufficient to overcome the rejection, because the amended claims are not enabled for treating liver cirrhosis/fibrosis not in early stages of liver cirrhosis (including liver cirrhosis of those specific liver diseases recited in new claims 20 and 22) for the reasons indicated above. With regard to Applicant’s arguments based on the disclosure of the published patent application (paras 0030-31, 0042, 0094 and Fig. 9), the disclosed data are obtained from in vitro cultured HSC cell line and they show only elevated levels of amyloid beta in supernatant of cell culture upon treatment of sacubitrilat/LBQ657 (an neprilysin inhibitor), but not attenuation of fibrotic progression. These in vitro cell culture data are not sufficient to provide the predictability or enablement for the entire scope of the claimed method, because there is no animal work in the specification to show effective attenuation or improvement of scarring or fibrotic progression in later stages of liver cirrhosis (especially final and clinically irreversible stages of liver cirrhosis) upon treating an animal with sacubitril.
Applicant’s arguments in the paragraph spanning pages 6 and 7 of the 09/05/2025 response are based on the Declaration under 37 CFR 1.132 by Inventor Danielyan. However, this 37 CFR 1.132 declaration is insufficient to overcome the rejection of claims 13-15 and 18 under 35 U.S.C. 112(a) for the following reasons.
The in vivo mouse works as well as related in vitro cell culture tests in the declaration provide factual evidence for enablement of the claimed method of preventing liver fibrosis or cirrhosis by using sacubitril (or its active metabolite). However, the declaration does not provide factual evidence to support later stages of liver cirrhosis (especially those final and clinically irreversible stages of liver cirrhosis) can be treated by administering sacubitril to an animal subject. There is no data to show extensive scarring/fibrosis in later or clinically irreversible stages of liver cirrhosis can be effectively improved or reversed by sacubitril treatment in an animal subject.
In response to Applicant’s arguments about state of the art in pages 7-8 of the 09/05/2025 response, Examiner disagree with Applicant’s interpretation about teachings of Reul. Applicant failed to submit the English-translated version for the entire document of Reul. However, English abstract of Reul clearly describes the investigation based on animals having liver cirrhosis, and demonstrates that in absence of neprilysin the animals have less liver fibrosis due to inhibitory effect of neuropeptide Y over liver fibrosis, and the neprilysin is the key to control levels of neuropeptide Y since neprilysin is the enzyme that cleaves and inactivates neuropeptide Y. These findings of Reul indicates that the neprilysin inhibitor/sacubitril could be critical for treating liver fibrosis in patients, because sacubitril inhibits neprilysin, which consequently prevents neuropeptide Y from being cleaved and inactivated by neprilysin, thus results in high levels of neuropeptide Y, which in turn inhibit liver fibrosis and lead to less liver fibrosis in the patients. Therefore, Reul expressively teaches (at the end of the abstract) a method of using a composition comprising an neprilysin inhibitor/sacubitril (combined with angiotensin II receptor blocker) as a therapy agent for treatment of early stages of liver cirrhosis. With regard to Applicant’s arguments based on inventors’ data included in the declaration, Examiner reminds Applicant that the declaration only provides data for preventing liver cirrhosis in mouse models, and there are no data from a liver fibrosis animal model to support or confirm a therapeutic effect of sacubitril for treating any later stages of liver cirrhosis in the claimed method. With regard to Applicant’s arguments based on Zhang, regardless of whether serious liver injury is caused by effect of valsartan, this incidence indicates the presence of sacubitril failed to prevent the serious liver injury from happening and the outcome of administering sacubitril could be unpredictable. Thus, sufficient animal work should be provided to support the enablement of the instantly claimed method for treating any stages of liver cirrhosis, especially those final and clinically irreversible stages of liver cirrhosis. With regard to Applicant’s arguments based on literature publications Suzuki et al. and Fabris et al., Examiner noted that data of improving liver functions in these publications are consistent with the teachings of Reul about treating early stages of liver cirrhosis as well as the claimed method of preventing liver cirrhosis by using a combination of an neprilysin inhibitor/sacubitril and an angiotensin II type 1 receptor blocker/valsartan. However, these publications failed to support the enablement of the claimed method of using sacubitril for treating any later stages of liver cirrhosis (especially those final and clinically irreversible stages of liver cirrhosis).
In response to Applicant’s arguments in page 8/para 3 of the 09/05/2025 response, Examiner notes that although meaning of the “pharmaceutically effective amount” is well understood in the art, a specifically-defined effective amount of sacubitril for treating ang later stages of liver cirrhosis in the claimed method is not disclosed in the specification. Further, although sacubitril is a known drug, it is not routine in the art to use sacubitril for treating later stages of liver cirrhosis, especially liver cirrhosis in most severe and clinically irreversible stages. Neither the prior art nor the specification provides any guide and information about how to obtain a pharmaceutically effective amount for effectively treating such later stages of liver cirrhosis. Without specific guide and information one of ordinary skill in the art would not be able to determine an effective amount through simple and routine dose-finding processes, without undue experimentation. Thus, the entire scope of the claimed method is not enabled.
In response to Applicant’s arguments in page 8/last para of the 09/05/2025 response, neither the specification nor Applicant’s declaration provides any factual evidence to demonstrate that any stages of liver cirrhosis (including most severe and clinically irreversible stages of liver cirrhosis) in an animal subject can effectively treated by administering sacubitril to the animal subject. Overall, neither the specification nor the prior art enable the entire scope of the claimed invention for all the reasons indicated above.
Applicant's arguments about the rejection of Claims 15 and 18 under 35 U.S.C. 112(a) for not complying with written description requirement in the 09/05/2025 response (page 9) have been fully considered but they are not persuasive. As Examiner explained in the rejection and in the response above (pages 16-17), the support for the limitation “a pharmaceutically effective amount” recited in the claims is not found in the specification. It is not routine in the art to use a pharmaceutically effective amount of sacubitril for treating any late stages of liver cirrhosis, especially liver cirrhosis that is in most severe and clinically irreversible stages. Neither the prior art nor the specification provides any guide and information about how to obtain a pharmaceutically effective amount for effectively treating such late stages of liver cirrhosis. Therefore, the full breadth of “a pharmaceutically effective amount” encompassed by the claims do not meet the written description provision of 35 USC 112, first paragraph.
Applicant's arguments about the rejection of Claims 13-14 under 35 U.S.C. 103 over Thum et al. in the 09/05/2025 response (page 10) have been fully considered but they are not persuasive for the following reasons. First, Applicant’s argument that the [0045] of Thum et al. refers to sacubitril in a non-limiting list in page 10/para 2 of the response is misleading and not persuasive. In contrary to Applicant’s argument, Thum et al. specifically teach an example of medication in the [0045] (see last 3 lines), in which only a single agent sacubitril is referred as the neprilysin inhibitor and there is no non-limiting list cited for the inhibitor. With regard to Applicant’s arguments based on using sacubitril for treating liver fibrosis or cirrhosis and for preventing degradation of amyloid beta peptides (in page 10 of the response), it is noted that the use of sacubitril for treating liver diseases and preventing amyloid degradation is directed to the intended use of the claimed invention and it does not limit the structure of the claimed sacubitril or composition thereof in the claims 13 and 14. Sacubitril or composition thereof taught by Thum et al. has the same structure as the claimed sacubitril/composition, thus meeting the limitation recited in the claims. With regard to Applicant’s arguments based on Thum et al. do not use Sacubitril alone for medical treatment in page 10 of the response, these arguments are based on features not recited in the claims. Examiner notes that the instant claims do not recite any limitation to require that Sacubitril is the only agent in the claimed composition. Therefore, the claimed composition has no novelty and the claims 13-14 are obvious over Thum et al. for all the reasons indicated above.
Applicant's arguments about the rejection of Claims 13-15 and/or 18 under 35 U.S.C. 103 over Reul either alone or combined with Thum et al. in the 09/05/2025 response (pages 10-11) have been fully considered but they are not persuasive.
First, Applicant’s argument in page 10/paras 2 and 4-5 of the 09/05/2025 response are not persuasive for the reasons indicated above. With regard to Applicant’s arguments about teachings of Reul in pages 10-11 of the response, these arguments are misleading and not persuasive. Examiner notes that Reul expressively teaches a method of using the combination of neprilysin inhibitor and angiotensin II type 1 receptor blocker as medication for treating early stages of liver cirrhosis, as Reul summarized in the abstract of the dissertation (see last 3 lines of the abstract), which is a part of the claimed substances of the instant application. The method taught by Reul is not a speculative suggestion, rather it is supported by the animal research data summarized in the abstract. With regard to Applicant’s arguments about the effect of neprilysin inhibitor alone or using isolated sacubitril as therapy was not taught by cited prior art (in page 11 of the response), these arguments are based on features not recited in the claims for the reasons indicated above. With regard to Applicant’s arguments based on Zhang, these arguments are moot because Zhang is not a recited prior art and is not relevant to the 103 rejections of record. Further, regardless of what Zhang teaches, nothing can change the fact that Reul teaches using a pharmaceutical composition comprising neprilysin inhibitor for treating early stages of liver cirrhosis. Furthermore, Reul expressively teaches a combination of sacubitril (as neprilysin-inhibitor) and valsartan (as angiotensin-II-receptor blocker), at least in page 81/last para (where English is used), which further supports Examiner’s position that it would have been obvious to use sacubitril as neprilysin-inhibitor in the method of Reul for treating early stages of liver cirrhosis.
In response to Applicant’s arguments based on the combination of Reul and Thum in page 11 of the response, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). As indicated above in the 103 rejection, the differences between the claimed method and the method of Reul are that the English abstract of Reul does not expressively mention sacubitril as the neprilysin-inhibitor and including a pharmaceutically acceptable excipient in the composition. The test for obviousness is not whether the features of Thum may be bodily incorporated into the method of Reul; nor is it that the claimed invention must be expressly suggested in any one or all of Reul and Thum. Rather, the test is what the combined teachings of Reul and Thum would have suggested to those of ordinary skill in the art. As indicated above, it is common practice in the art to use sacubitril as a neprilysin-inhibitor and to include a pharmaceutically acceptable excipient in a pharmaceutical composition. Thus, the claimed method would have been obvious over the cited prior art for the reasons indicated above. The cited prior art provides motivation in and of itself, along with a reasonable expectation of success, because Reul expressively teach using neprilysin-inhibitor for treating early stages of liver cirrhosis and medications comprising neprilysin-inhibitor are routinely used in clinical practice; and Thum demonstrates it is a common practice to use sacubitril as a neprilysin-inhibitor and include a pharmaceutically acceptable excipient in medications or pharmaceutical compositions.
Overall, the conclusion of the obviousness of the claims 13-15 and 18-22 has been established for all the reasons indicated above. The claimed invention has no novelty.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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 date of this final action.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Qing Xu, Ph.D., whose telephone number is (571) 272-3076. The examiner can normally be reached on Monday-Friday from 9:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath N. Rao, can be reached at (571) 272-0939. Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to the receptionist whose telephone number is (571) 272-1600.
/Qing Xu/
Patent Examiner
Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656
Prosecution Insights