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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/21/2026 has been entered. It is noted that a new Examiner, George Lountos, is examining the case.
Claim Status
Claims 1-17 and 19 are pending.
Claims 18 and 20 are canceled.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/27/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Priority
Applicants claim domestic priority to provisional application 63/050,008 filed on 07/09/2020 is acknowledged.
Claim Rejections - 35 USC § 103
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.
(previous rejection, maintained) Claims 1-5, 7-8, 10-16, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Tarsio, US 20200181224 A1 (hereby referred to as Tarsio), in view of Zheng (hereby referred to as Zheng), Henriksen (hereby referred to as Henriksen), and Xia (hereby referred to as Xia).
Tarsio teaches a method for treating diseases comprising administering of a pharmaceutically effective amount of a soluble recombinant human alpha-klotho protein (Tarsio, abstract; [43]). Tarsio teaches that the route of administration may be intravenous infusion or subcutaneous injection (Tarsio, [189]). Tarsio also teaches that the soluble human alpha-klotho protein may be modified by the fusion of additional peptides, proteins, or chemical groups in order to extend its half-life and to increase solubility (Tarsio, [121]). Additionally, SEQ ID NO: 22 disclosed by Tarsio (Tarsio, [43]) was found to be a 99% identity match to the entirety of SEQ ID NO: 1 of the instant application.
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Additionally, Tarsio teaches that the soluble human alpha-klotho protein may comprise both a KL1 and KL2 domain (Tarsio, [2]) or solely a KL1 domain while being devoid of a KL2 domain (Tarsio, [3]). Tarsio also teaches administering the klotho protein in combination with Rapamycin (Tarsio, [257]), which according the instant disclosure is an mTOR pathway inhibitor (instant specifications filed 03/23/2022, [5]). Tarsio does not teach that the method is for treating a severe acute respiratory syndrome-related coronavirus (SARS-CoV) infection in a subject in need thereof.
Zheng teaches that increased IL-6 levels and cytokine storms (also known as cytokine release syndrome) are considered as the major cause of illness and death due to COVID-19 (Zheng, abstract; pg. 5 [3]). Zheng suggests using an mTOR inhibitor (rapamycin) treatment along with an IL-6 inhibitor for SARS-CoV-2 treatment (Zheng, pg. 5, [3]).
Henriksen teaches that patients infected with SARS-CoV-2 had higher blood plasma levels of IL-6 (Henriksen, pg. 5, [2]). Additionally, Henriksen teaches that IL-6 blockade therapy using an IL-6 inhibitor has resulted in beneficial effects for patients with severe SARS-CoV-2 pneumonia (Henriksen, pg. 6, [1]). Henriksen also teaches
that IL-6 inhibitors are currently considered to be well tolerated and safe in general (Henriksen, pg. 6, [2]).
Xia teaches that Klotho protein is an IL-6 inhibitor (Xia, pg. 5, [2]).
The teachings of Zheng, Henriksen, and Xia, would have motivated a person of ordinary skill in the art to use the method taught by Tarsio to treat COVID-19 and/or SARS-CoV-2 infection in a subject in need thereof. The teachings of Zheng suggest the use of an mTOR inhibitor and IL-6 inhibitor to treat SARS-CoV-2 infection (Zheng, pg. 5, [2]). Additionally, the method taught by Tarsio is already intended to be utilized to treat risk factors associated with severe outcomes of SARS-CoV-2 infection (Tarsio, [387]). These risk factors include: COPD, acute kidney injury, chronic kidney disease, cancer, hypertension, obesity, diabetes, and cognitive disorders (specifications filed 03/23/2022, tables 3-4). A person having ordinary skill in the art would have a reasonable expectation of success for the following reasons: 1) klotho protein was known at the time to be an IL-6 inhibitor (Xia, pg. 5, [2]). 2) IL-6 blockade therapy using an IL-6 inhibitor resulted in beneficial effects for patients with SARS-CoV-2 (Henriksen, pg. 6, [1]). 3) IL-6 inhibitors were known in the art to be well tolerated and generally safe (Henriksen, pg. 6, [2]). Therefore, it would have been obvious to one of ordinary skill in the art to utilize the method taught by Tarsio for the treatment of SARS-CoV-2 in a subject in need thereof, as in instant claim 1. Furthermore, the method taught by Tarsio encompasses the limitations of claims 3-5, 7-8, 10-16, and 20. Accordingly, claims 1-5, 7-8, 10-16, and 20 are rejected.
(previous rejection, maintained) Claims 1-3, and 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Tarsio, Zheng, Henriksen, and Xia as applied to claim 1 above, and further in view of Hsia, US 20180207107 A1 (hereby referred to as Hsia).
The teachings of Tarsio, Zheng, Henriksen, and Zia as they apply to claim 1 are stated above.
Hsia teaches a method of treating infection, inflammatory disease, or acute respiratory distress syndrome in a human subject comprising administering a therapeutically effective amount of a recombinant alpha-klotho protein or a DNA encoding the alpha-klotho protein (Hsia, [13], claim 19).
The teachings of Tarsio, Zheng, Henriksen, and Xia, would have led one of ordinary skill in the art to utilize the method taught by Hsia to treat SARS-CoV-2 infection in a subject in need thereof. The method taught by Hsia is already directed towards the use of treating a lung infection (Hsia, [9]). As stated above, klotho protein is known to be an IL-6 inhibitor (Xia, pg. 5, [2]). It is known that increased IL-6 levels in a subject infected with SARS-Cov-2 were associated with more severe outcomes (Zheng, abstract; pg. 5 [3]). Furthermore, Henriksen teaches that IL-6 inhibitor treatment resulted in beneficial effects for patients with severe SARS-CoV-2 pneumonia (Henriksen, pg. 6, [1]). Additionally, the method taught by Hsia may be formulated for administration via inhalation or aerosol delivery, allowing for more rapid and less invasive absorption (Hsia, [4]; [8]). Therefore, it would have been obvious to one of ordinary skill in the art, based on the above teachings, the utilize the method taught by Hsia to treat SARS-CoV-2 infection in a subject in need thereof. Accordingly, claims 1-3 and 9-10 are rejected.
(previous rejection, maintained) Claims 1 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Tarsio, Henriksen, Zheng, and Xia as applied to claim 1 above, and further in view of Lynch (hereby referred to as Lynch).
The teachings of Tarsio, Henriksen, Zheng, and Xia as they apply to the method of claim 1 are shown above.
Lynch teaches protein purification from large pools of blood plasma from 1,000 donors or more (Lynch, pg. 1, [1-2]).
It would have been obvious to one of ordinary skill in the art to use the method of purification taught by Lynch in order to source the Klotho protein for use in the method taught by Tarsio, Zheng, Henriksen, and Xia as it applies to claim 1. A person of ordinary skill in the art would be motivated to use large pool protein purification because Lynch teaches that protein purification from large pools of plasma is an economical way of obtaining plasma proteins (Lynch, pg. 1, [1]). Additionally, Lynch teaches that purification of proteins from large pools of plasma increases the consistency of the product (Lynch, pg. 1 [1]). A person of ordinary skill in the art would have a high expectation of success because human plasma proteins have been isolated from large
pools of donated plasma since the 1950s (Lynch, pg. 1, [1]). Furthermore, Tarsio teaches that klotho protein is found in human blood plasma (Tarsio, [140]). Therefore, it would have been obvious to use the plasma protein purification taught by Lynch in order to source to klotho protein for use in the method taught by Tarsio, Zheng, Henriksen, and Xia, as applied to claim 1.
(previous rejection, maintained) Claims 1 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Tarsio, Zheng, Henriksen, and Xia as applied to claim 1 above, and further in view of Glass, US 20090192087 A1 (hereby referred to as Glass).
The teachings of Tarsio, Zheng, Henriksen, and Xia as they apply to claim 1 are shown above. The above references do not teach that the klotho polypeptide is a beta- klotho polypeptide.
Glass teaches a method of treating a disease in an individual by administering a
pharmacologically effective amount of beta-klotho polypeptide (Glass, [142]). Glass
teaches that the method is intended for the treatment of diseases or conditions such as:
cancer, obesity, high blood pressure, type II diabetes, impaired kidney function, stroke,
and pulmonary emphysema (Glass, [47]; [193]).
It would have been obvious to one of ordinary skill in the art to use the beta-
klotho polypeptide taught by Glass for the method of claim 1, as taught by Tarsio,
Zheng, Henriksen, and Xia above. One would be motivated to combine the above
teachings because the beta-klotho polypeptide taught by Tarsio is intended to treat
many of the same diseases or conditions that Tarsio intends to treat using an alpha-
klotho. A person having ordinary skill in the art would have a reasonable expectation of
success for the following reasons: 1) klotho protein was known at the time to be an IL-6
inhibitor (Xia, pg. 5, [2]). 2) IL-6 blockade therapy using an IL-6 inhibitor resulted in
beneficial effects for patients with SARS-CoV-2 (Henriksen, pg. 6, [1]). 3) IL-6 inhibitors
were known in the art to be well tolerated and generally safe (Henriksen, pg. 6, [2]).
Therefore, it would have been obvious to a person of ordinary skill in the art to use the
beta-klotho polypeptide taught by Glass for the method of claim 1 as taught by Tarsio,
Zheng, Henriksen, and Xia. Accordingly, claims 1 and 17 are rejected.
Response to Arguments
Applicant's arguments filed 01/21/2026 have been fully considered but they are not persuasive.
Applicants argue that the cited references do not teach or suggest administrating a therapeutically effective amount of Klotho polypeptide to a subject with a SARS-CoV infection and that there was no reasonable expectation of successfully treating a SARS-CoV infection by administrating Klotho (see pg. 6 ). Applicants argue that at the time the present application was filed, the evidence at the time did not support a hypothesis that an IL-6 inhibitor would be an effective therapy for SARS-CoV infection because it was reported that IL-6 levels in COVID-19 were not significantly elevated. Applicants also argue that even if a reasonable expectation that IL-6 blockade would be effective for treating SARS-CoV infection, Klotho is not an IL-6 inhibitor and thus cannot cause IL-6 blockade (see pg. 7). Applicants further argue that at the time of filing, the evidence suggested that IL-6 levels were not significantly elevated in COVID-19 patients and the Applicants refer to the reference of Sinh et al. (JAMA Intern Med. 180(9):1152-5(2020), included in the IDS) which does not support that cytokine storm is associated with COVID-19 (see pg. 7-9).
Applicants also argue that the claim that patients infected with SARS-CoV-2 exhibit elevated blood plasma levels of IL-6 as taught by Henriksen is unsubstantiated in comparison to data from the Sinha publication (see pg. 9). Applicants also argue that the statement by Henriksen that “remarkable beneficial effects of IL-6 blockade using a IL-6 receptor inhibitor has been described in patients with severe SARS-CoV-2 pneumonia cannot be relied upon and that an IL-6 receptor inhibitor would not function analogously to an IL-6 inhibitor and that the Henriksen reference frames IL-6 inhibition as a hypothesis to be explored rather than a treatment strategy that has been validated (see pg. 9). Applicants also argue that regardless of whether a reasonable expectation existed at the time of filing that IL-6 blockade would be an effective treatment of SARS-CoV infection, the Applicants argue that the logic to use Klotho as an effective treatment for SARS-CoV infection fails because Klotho is not an IL-6 inhibitor (see pg. 10). Applicants also argue that Xia does not teach that IL-6 is an inhibitor but rather has a potent role in inhibiting IL-6 production.
The Examiner does not find the arguments persuasive.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
Additionally, according the MPEP 2145 (IV), “One cannot show nonobviousness by attacking references individually where the rejections are based on a combination of references”.
Regarding claim 1, the term “treating” is not specifically defined in the specifications. Without importing limitations from the specifications into the claims, the following definitions from the specifications are noted:
"As used herein, the term "polypeptide treatment" refers to any therapeutic approach of providing a polypeptide (e.g., a protein and/or enzyme) to a subject to relieve, diminish, or prevent the occurrence of one or more symptoms of a disease (e.g., a coronavirus infection) and/or a condition associated with a deficiency or absence of the polypeptide in the subject." (specifications filed 03/23/2022, [77]).
"As used interchangeably herein, the term "treatment" or "therapy" generally means obtaining a desired physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or condition or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for an injury, disease, or condition and/or amelioration of an adverse effect attributable to the injury, disease or condition includes arresting the development or causing regression of a disease or condition”. (see specifications filed 03/23/2022).
MPEP section 2111 states "The Patent and Trademark Office ("PTO") determines the scope of claims in patent applications not solely on the basis of the claim language, but upon giving claims their broadest reasonable construction "in light of the specification as it would be interpreted by one of ordinary skill in the art." In re Am. Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1364[, 70 USPQ2d 1827, 1830] (Fed. Cir. 2004). Indeed, the rules of the PTO require that application claims must "conform to the invention as set forth in the remainder of the specification and the terms and phrases used in the claims must find clear support or antecedent basis in the description SO that the meaning of the terms in the claims may be ascertainable by reference to the description." 37 CFR 1.75(d)(1).
While the terms "polypeptide treatment", "treatment" or "therapy" are not recited explicitly recited in claim 1, one of ordinary skill in the art would understand that broad term of "treating", as presently recited in claim 1, would include completely or partially preventing a disease or condition or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for an injury, disease, or condition and/or amelioration of an adverse effect attributable to the injury, disease or condition and includes arresting the development or causing regression of a disease or condition, or generally means obtaining a desired physiologic effect.
Henriksen states that “it has been suggested that blockade may constitute a novel therapeutic strategy for other types of cytokine storm, such as the systematic inflammatory response syndrome including sepsis, macrophage activation syndrome and hemophagocytic lymphohistiocytosis. Remarkable beneficial effects of IL-6 blockade therapy using an IL-6 receptor inhibitor has been described in the patients with severe SARS-CoV2 pneumonia (Henricksen, pg. 6, [1]).
In consideration of the Applicant’s argument that the reference of Sinh et al. (JAMA Intern Med. 180(9):1152-5(2020), included in the IDS) does not support that cytokine storm is associated with COVID-19 (see pg. 7-9), before the time of filing and that the Examiner is not persuaded. Henriksen teaches that patients infected with SARS-CoV-2 had higher blood plasma levels of IL-6 (Henriksen, pg. 5 [2]). Zheng teaches that increased IL-6 levels and cytokine storms are considered major cause of illness and death due to COVID-19 (Zheng, abstract; pg. 5 [3]). Zheng teaches that IL-6 may play a key role in the cytokine storm-associated serious adverse outcomes and IL-6 blockade has been initiated to treat severe COVID-19 disease with respiratory failure (Zheng, abstract; pg. 5 [3]).
In response to the Applicants argument that the teaching of an IL-6 inhibitor by Xia is misinterpreted and that Klotho cannot cause IL-6 blockade, (see pg. 7) , Xia teaches that klotho overexpression could suppress IL-6 production in cells with or without inflammatory challenge (see pg. 3.4 Overexpression of Klotho Blunted TNF-alpha induced IL-6) thus the data do show that klotho has an inhibitory effect on IL-6 production. Additionally, Henriksen has shown that IL-6 blockade therapy using an IL-6 inhibitor resulted in beneficial effects for SARS-CoV-2 patients (see Henriksen, pg. 6, [1]). The prior art described goes against the Applicants argument that there would be no reasonable expectation that klotho would be effective for the treatment of a SARS-CoV infection because klotho is not an IL-6 inhibitor as Xia demonstrate that klotho has inhibitory effects on IL-6 production and Henriksen show that IL-6 blockade has beneficial effects for SARS-CoV-2 patients.
Conclusion
No claims are allowed.
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/GEORGE THEMISTOCLIS LOUNTOS/ Examiner, Art Unit 1652
/ROBERT B MONDESI/ Supervisory Patent Examiner, Art Unit 1652