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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Remarks
The amendments and remarks filed on 03/19/2026 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 Any previously presented objections or rejections that are not presented in this Office Action are withdrawn.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, 15, and 18-22 are pending.
Claims 13, 15, 18-19, and 21 are amended.
Claims 1-12, 14, and 16-17 are canceled.
Claims 13, 15, and 18-22 have been examined on the merits.
Priority
This application 17/449723 is a continuation of international patent application number PCT/EP2020/059486, filed on April 3, 2020, which claims priority under 35 U.S.C. 119(a)-(d) from German patent application DE 10 2019 108 825.9, filed on April 4, 2019.
Rejections - Withdrawn
The rejection of Claim 14 under 35 U.S.C. 112(d), for failing to further limit the subject matter of the claim upon which it depends, is withdrawn due to the cancellation of the claim filed on 03/19/2026.
The rejection of Claims 15 and 18-22 under 35 U.S.C. 112(a) as failing to comply with the written description requirement is withdrawn due to the amendment to the claims filed on 03/19/2026.
The rejections of claim 14 under 35 U.S.C. 103 over Thum et al. or over Reu in view of Thum et al. are withdrawn due to the cancellation of the claim filed on 03/19/2026.
Claim Rejections - 35 USC § 112, Second Paragraph
Claims 15 and 18-22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 15 is indefinite due to the recitation of “a method for preventing … and treating liver fibrosis … administering to a subject …a compound … sacubitril, thereby preventing liver fibrosis … and treating liver fibrosis”. It is noted that there are two distinct populations of the “subject” in the claimed method: a healthy subject population (not having the liver diseases) to be prevented by the claimed method; and a non-healthy subject population (having the liver diseases) to be treated by the claimed method. Accordingly, the claimed method is for preventing the diseases in the healthy subject population or for treating the diseases in the non-healthy subject population; and the administering compound/sacubitril to subjects would lead to two distinct outcomes in the two distinct populations: preventing the diseases in the healthy subject population or treating the diseases in the non-healthy subject population. However, the claim describes the method is for preventing and treating the liver diseases by administering compound/sacubitril to a subject, thereby preventing and treating the liver diseases. It is unclear how the claimed method can be applied for preventing and treating liver diseases at the same time; and how the diseases can be thereby prevented and treated at the same time in a healthy subject not having the diseases to be treated or in a non-healthy subject already having the diseases (not preventable). For the purpose of examination, the phrase is interpreted as: a method for preventing … or treating liver fibrosis … administering to a subject …a compound … sacubitril, thereby preventing liver fibrosis or liver cirrhosis or treating liver fibrosis”.
The claims 18-19 and 21 are indefinite due to the recitations of “a method for preventing … and treating liver fibrosis” and “thereby preventing liver fibrosis or liver cirrhosis and treating liver fibrosis” for the reasons indicated above. For the purpose of examination, the phrases are interpreted as: a method for preventing … or treating liver fibrosis” and “hereby preventing liver fibrosis or liver cirrhosis or treating liver fibrosis”, respectively.
The remaining claims are rejected for depending from an indefinite claim.
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 decreasing the probability for developing liver fibrosis or cirrhosis and for treating liver fibrosis by using sacubitril, does not reasonably provide enablement for a method for complete prevention of liver fibrosis/cirrhosis, and preventing or treating the claimed liver diseases by using sacubitril. 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 preventing liver fibrosis/cirrhosis or treating liver fibrosis, comprising a single step of administering to a subject a pharmaceutical composition comprising any amount of sacubitril; and the claims 20 and 22 define that the liver fibrosis is a liver disease selected from primary biliary cirrhosis, nonalcoholic steatohepatitis, alcohol hepatitis, and hepatocellular carcinoma. Claim 13 is directed to a pharmaceutical composition comprising sacubitril for use in prevention of liver fibrosis/cirrhosis or treating liver fibrosis.
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 preventing or treating liver fibrosis/cirrhosis in an animal. Examples in pages 14-23 of the specification only disclose multiple tests in in vitro cultured cell lines or isolated human tissues under in vitro conditions, which demonstrated levels of amyloid beta protein/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 either alone or in combination with angiotensin receptor antagonist/valsartan to a subject can completely prevent liver fibrosis/cirrhosis, or treat or prevent a liver disease of primary biliary cirrhosis, nonalcoholic steatohepatitis, alcohol hepatitis, or hepatocellular carcinoma. Only the declaration under 37 CFR 1.132 filed on 09/05/2025 by Inventor Danielyan (pages 6 and 7) shows data of in vivo mouse works by administering a combination of sacubitril and valsartan to a mouse model, which provide factual evidence for enablement of the claimed method for decreasing the probability for developing liver fibrosis/cirrhosis. However, there is no factual evidence in either the specification or the declaration to support that sacubitril, when being administered to a subject, can completely prevent liver fibrosis/cirrhosis or can treat/prevent liver fibrosis such as primary biliary cirrhosis, nonalcoholic steatohepatitis, alcohol hepatitis, and hepatocellular carcinoma. Furthermore, the specification does not provide any guidance or information regarding how to use the claimed method to reach the goal of completely preventing liver cirrhosis/fibrosis, or treating/preventing liver fibrosis such as primary biliary cirrhosis, nonalcoholic steatohepatitis, alcohol hepatitis, and hepatocellular carcinoma.
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 early stages of liver cirrhosis (liver fibrosis) can be treated by using a combination of a neprilysin inhibitor/sacubitril and an angiotensin II type 1 receptor blocker/valsartan. The teachings of the cited prior art suggest that liver fibrosis associated with liver diseases can be treated by using the combined sacubitril agent. However, there is no teaching or suggestion in the prior art indicating that sacubitril can be used for effectively treating or preventing primary biliary cirrhosis, nonalcoholic steatohepatitis, alcohol hepatitis, or hepatocellular carcinoma, per se. 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 to a subject no having the liver diseases could lack predictability, and liver diseases cannot be completely prevented by administering sacubitril.
The quantity of experimentation necessary. It is not routine in the art to use the neprilysin inhibitor/sacubitril for completely preventing liver fibrosis/cirrhosis in subjects, and treating/preventing the claimed liver diseases by using sacubitril, which include primary biliary cirrhosis, nonalcoholic steatohepatitis, alcohol hepatitis, and hepatocellular carcinoma. Neither the prior art nor disclosure of the specification shows that liver fibrosis/cirrhosis can be completely prevented in subjects and the liver diseases (e.g. primary biliary cirrhosis, nonalcoholic steatohepatitis, alcohol hepatitis, and hepatocellular carcinoma) can be treated or prevented by administering sacubitril to a subject. 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 completely preventing liver fibrosis/cirrhosis or treating/preventing liver diseases including primary biliary cirrhosis, nonalcoholic steatohepatitis, alcohol hepatitis, and hepatocellular carcinoma.
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 completely preventing liver fibrosis/cirrhosis and treating/preventing liver diseases including primary biliary cirrhosis, nonalcoholic steatohepatitis, alcohol hepatitis, and hepatocellular carcinoma. Neither the specification nor the prior art enable the entire scope of the claimed invention.
Claim Rejections - 35 USC § 103
Claim 13 is 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).
Thum et al. teach an example of medicament suitable for preventing or treating cardiac disorders/heart failure, specifically, a neprilysin-inhibitor, or a combination of a neprilysin-inhibitor, i.e. sacubitril, and an angiotensin-II-receptor blocker, i.e. valsartan (para 0045). It is noted that the limitations for prevention and treatment of liver fibrosus and/or cirrhosis in the preamble of claim 13 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 these claimed limitations. Regarding the newly added limitation “the sacubitril is monotherapy sacubitril without valsartan”, this limitation defines one of the compounds to be comprised in the claimed composition. However, the claim does not recite any limitation to define that the sacubitril is the only active compound (monotherapy) comprised in the entire claimed composition, or to define that the entire claimed composition does not comprises valsartan. Examiner notes that the claim 13 uses “comprising” (not “consisting of”) as the transitional phrase for the claim, which indicates the claimed composition is open to comprise any additional compound(s) (including valsartan). As such, the scope of the claim encompasses a composition comprising sacubitril and valsartan. Thus, the medicament composition comprising sacubitril and valsartan, taught by Thum et al., meets the claimed limitations. Moreover, Thum et al. teach that the medicament may comprise only a neprilysin-inhibitor (i.e. not combined with other active agents) (see para 0045, line 5). As such, it would have been obvious to provide neprilysin-inhibitor, e.g. sacubitril, as a single active agent in the medicament composition of Thum et al.
Regarding the limitation of the pharmaceutically acceptable excipient in the claim, the recited acceptable excipient has an extremely broad scope, which can be any amount of any non-active components such as solvents; and even water can read on the claimed “pharmaceutically acceptable excipient”. Thum et al. teach the composition is administered by injection such as intravenous injection (para 0042). It is a common practice in the art to use a solvent/water as a pharmaceutically acceptable carrier/excipient for injectable pharmaceutical compositions. Thus, it would have been obvious to provide a neprilysin-inhibitor/sacubitril as a single active agent or in combination with valsartan along with water as a pharmaceutically acceptable excipient in the medicament composition of Thum et al. Furthermore, in view of the paras 0039 and 0015 of Thum et al., it would have been obvious to add a pharmaceutically acceptable excipient to the medicament composition 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).
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. Thus, the neprilysin inhibitor taught by Reul is a compound that inhibits degradation of amyloid beta protein). 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 that an neprilysin inhibitor in combination with an angiotensin II type 1 receptor blocker is applied as a therapy agent (i.e. a pharmaceutical composition) for treatment of early stages of liver cirrhosis, given this combined therapy agent is already used in routinely clinical practice for heart treatment (abstract, last para). As such, Reul teaches/suggests a method for treating early stages of liver cirrhosis by administering a neprilysin inhibitor combined with an angiotensin II type 1 receptor blocker to a subject in need thereof. It is noted that an early stage (reversible) of liver cirrhosis comprises liver fibrosis, as evidenced by the disclosure of the specification (para 0008), and by the teachings of Reul, which demonstrates that neprilysin inhibition/reduction leads to less fibrosis of liver tissue. As such, the treating early stages of liver cirrhosis in the method of Reul comprises treating liver fibrosis, thus meeting the claimed limitation about treating liver fibrosis in the claims 15, 18-19 and 21.
In the English-translated version of Reul (newly submitted by applicant on 03/19/2026), Reul further teaches using a combination of the neprilysin inhibitor, sacubitril, and the AT1R antagonist, valsartan, for determining its impact on heart failure and Reul demonstrated the superior effect of the combined agent (page 29, para 1).
The method taught by Reul differs from the method of the claims 15 and 18-22 in that Reul 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 use sacubitril and valsartan as the combination of neprilysin inhibitor and the angiotensin II receptor blocker in a pharmaceutical composition comprising a pharmaceutically acceptable excipient in the method of Reul for treating early stages of liver cirrhosis and liver fibrosis by administering the pharmaceutical composition to a subject in need thereof, because a combination of sacubitril and valsartan is commonly used in clinic practice for treating cardiac disorders/heart failure, as supported by Reul and Thum et al.; and Reul expressively teaches applying this kind of combined agent for treating early stages of liver cirrhosis (and liver fibrosis). Furthermore, it is a common practice in the art to include a pharmaceutically acceptable excipient/carrier in a pharmaceutical composition for treating patients, as supported by Thum et al.
Regarding the limitation “the sacubitril is monotherapy sacubitril without valsartan” newly added to the claims 15, 18-19, and 21, this limitation defines one of compounds to be comprised in the claimed composition. As indicated above, the claim does not recite any limitation to define that the sacubitril is the only active compound (monotherapy) comprised in the entire claimed composition, or to define that the entire claimed composition does not comprises valsartan; and the claims use “comprising” as the transitional phrase, such that the claimed composition is open to comprise any additional compound(s) (including valsartan). As such, the scope of the claim encompasses a composition comprising sacubitril and valsartan. Thus, the pharmaceutical composition comprising sacubitril and valsartan suggested by Reul and Thum et al., meets the claimed limitations.
Regarding the claims 20 and 22, Reul and Thum et al. suggest a method of administering a pharmaceutical composition comprising sacubitril and valsartan for treating early stages of liver cirrhosis and liver fibrosis. 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 and/or liver fibrosis associated with or caused by liver diseases such as primary biliary cirrhosis, nonalcoholic steatohepatitis, alcohol hepatitis, and hepatocellular carcinoma, recited in the claims, because any early stages of liver cirrhosis and liver fibrosis 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 rejection of Claim 14 under 35 U.S.C. 112(d) in the response filed on 03/19/2026 (page 4) have been fully considered but they are moot because the rejection has been withdrawn for the reasons indicated above.
Applicant's arguments about the rejection of Claims 15 and 18-22 under 35 U.S.C. 112(a) for lacking full scope of enablement in the 03/19/2026 response (page 4) have been fully considered but they are not persuasive because Applicant’s amendment to the claims is not sufficient to overcome the rejection (please see pages 5-8 for details).
Applicant's arguments about the rejection of Claims 15 and 18-22 under 35 U.S.C. 112(a) as failing to comply with the written description requirement in the 03/19/2026 response (page 5) have been fully considered but they are moot because the rejection has been withdrawn for the reasons indicated above.
Applicant's arguments about the rejection of claims 13-14 under 35 U.S.C. 103 over Thum et al. in the response filed on 03/19/2026 (page 5) have been fully considered but they are not persuasive. As indicated above, the claim 13 does not recite any limitation to limit sacubitril as a monotherapy agent in the entire claimed composition; and given that the claim uses “comprising” as the transitional phrase, the claimed composition is open to comprise any additional compounds (e.g. valsartan or oligonucleotide). Thus, the medicament composition of Thum et al. meets the claimed limitations about sacubitril, as indicated above. With regard to the claimed limitations about preventing or treating liver diseases, these limitations are directed to the intended use of the claimed composition and they do not limit the structure of the claimed composition, as indicated above. Examiner notes that the claim 13 has an extremely broad scope, which only recites an undefined amount of sacubitril along with an undefined pharmaceutical acceptable excipient at any undefined amount. Sacubitril is a drug well known and commonly used in the art, as evidenced by Thum et al. and Zhang et al. (of record). The claimed composition has no novelty.
Applicant's arguments about the rejection of claims 13-15 and 18-22 under 35 U.S.C. 103 over Reul in view of Thum et al. in the 03/19/2026 response (pages 6-7) have been fully considered but they are not persuasive. First of all, Applicant’s arguments based on the claimed composition comprising sacubitril without valsartan in page 6/para 2 and the para spanning pages 6-7 of the response are not persuasive for the reasons described above; and the combination of sacubitril and valsartan in the composition suggested by Reul meets the claimed limitation about sacubitril, as indicated above.
In response to Applicant’s remaining arguments in the para spanning pages 6-7 of the response, the abstract of Reul summarizes major findings from his investigations, which expressively teaches a method of using a combination of neprilysin inhibitor (sacubitril) and angiotensin II type 1 receptor blocker (valsartan) as medication for treating early stages of liver cirrhosis. The method taught by Reul is not a speculative suggestion, rather it is supported by solid evidence and results obtained from in vivo animal work, as explained in details by Examiner in the previous office action of 1/22/2026 (see page 15/last para and page 16/first half of para 1). Furthermore, Examiner reminds Applicant that the specification of the instant application does not disclose any work to support that administering sacubitril to a subject in the claimed method is effective at treating liver fibrosis or liver diseases, specifically including primary biliary cirrhosis, nonalcoholic steatohepatitis, alcohol hepatitis, and hepatocellular carcinoma, as recited in the instant claims. The specification of the instant application does not provide any in vivo animal work evidence for a therapeutic effect of sacubitril for liver fibrosis or liver diseases, and it merely discloses a simplified in vitro assay on cultured cell lines for determining levels of amyloid beta in the supernatant of cell culture, which has no way to mimic complexed situations in an animal subject. The disclosure of fundamental in vivo animal work of Reul is certainly more superior to the disclosure of simplified in vitro cell line assay of the instant application, with regard to providing support for methods of treating liver fibrosis or cirrhosis.
Overall, the conclusion of the obviousness of the amended claims 13, 15 and 18-22 has been established for all the reasons indicated above.
Conclusion
No claim is in condition for allowance.
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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
Prosecution Insights