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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed 08/19/2025.
Claims 14 and 21-22 are amended, claims 16-18, 23, 34, and 36 are canceled, claims 37-41 are newly added, and claims 14 and 41 are independent as set forth in the claim set filed 08/19/2025.
Therefore, claims 14, 21-22, 24-30, 32-33 and 37-44 are examined on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed parent provisional applications 63/305,836 filed 02/02/2022, 63/188,652 filed 05/14/2021, and 63/146,538 filed 02/05/2021 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is February 05, 2021.
Response to arguments
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112 (a) Written Description
The rejection of claims 14, 16-18, 21-30, and 32-36 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn.
Applicant’s arguments and amendments filed 08/19/2025 have been considered and are persuasive regarding the rejection as previously set forth. Particularly, Applicant has amended to specify a dosage as well as the specific therapeutic effects of the therapy.
Claim Rejections - 35 USC § 112 (b)
The rejection of claims 14, 16-18, 21-30, and 32-36 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
Applicant’s arguments and amendments filed 08/19/2025 have been considered and are persuasive regarding the rejection as previously set forth. Particularly, Applicant has amended to no longer recite the term “significant” and determined an amount to provide the claimed vector within the method in the claim set newly filed. Therefore, the metes and bounds of the invention have been defined.
Claim Rejections - 35 USC § 112 (d)
The rejection of claims 16-18, 34 and 35 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being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends is withdrawn.
Applicant’s arguments and amendments filed 08/19/2025 have been considered and are moot in light of the cancelation of all claims rejected under 112(d).
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Claims 14, 21-22, 24-30, 32-33 remain rejected and new claims 41-44 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
a treatment method for reducing hair loss in mice, increasing number of mitochondria, and resistance in body weight loss through intranasal or intraperitoneal injection with 1 x 105 PFU/mouse of a genetically engineered cytomegalovirus (CMV) vector comprising telomerase reverse transcriptase (TERT) or follistatin (FS344) , does not reasonably provide enablement for
a method of treatment with a dosage of at least 1 x 105 PFU administered to any subject a recombinant CMV Vector comprising one or more exogenous donor genes (e.g., hTERT, hFST, KLOTHO, Dsup, PGC1α and others) including TERT or/and FS344, wherein the recombinant CMV viral vector is administered in an amount that provides the subject one or more of increased glucose tolerance, decreased glycosylated hemoglobin, increased physical coordination, increased telomere length, reduced age-related hair loss, increased resistance to loss in body weight, increased life span, increased mitochondria in skeletal muscle, increased mitochondria in heart muscle, or an increase in markers of autophagy. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 08/19/2025.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention. If not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d 731, 737, 8 USPQ2ds 1400, 1404 (Fed. Cir. 1988)). Furthermore, USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
The Breadth of the Claims and The Nature of the Invention
The claims are directed towards a method of treating an age related disease through intranasal or injectable administration of a dosage of at least 1 x 105 PFU of CMV viral vectors encoding any one or combination of genes including: telomerase reverse transcriptase (TERT) gene, a follistatin- 344 (FST) gene and a klotho (KL) gene and additional genes, (e.g., hTERT, hFST, KLOTHO, Dsup, PGC1α and others) to any subject that are able to provide one or more of increased glucose tolerance, decreased glycosylated hemoglobin, increased physical coordination, increased telomere length, reduced age-related hair loss, increased resistance to loss in body weight, increased life span, increased mitochondria in skeletal muscle, increased mitochondria in heart muscle, or an increase in markers of autophagy.
The specification provides examples of a reduction in hair loss, increased telomere length, and a resistance in body weight loss (Example 10 and 11) but only in mice and only at a disclosed dosage of 1 x 105 PFU per mouse with monthly injections.
To figure out a way to translate the dosage to humans or any other animal would require undue trial and error experimentation, the outcome of which is highly unpredictable.
The specification discloses the subject, and even “patient”, may be any animal (para. 0110).
Thus, the claims are broad for reasonably encompassing an enormous genus of about 1,000,000 species of animals (Kingdoms of Life, waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021), wherein the mammalian sub-genus reasonably encompasses some 6,400 species (including humans), distributed in about 1,200 genera, about 152 families and about 29 orders (Mammal, en.wikipedia.org/wiki/Mammal, last visited August 31, 2022). The claims also encompass a genus of gene combinations in addition to TERT or/and FS344 that are able to provide to the claimed subject one or more of the properties recited in independent claims 14 and 41.
In conclusion, the specification fails to provide any guidance as to how an artisan would have dealt with the art-recognized limitations of the claimed method commensurate with the scope of the claimed invention and therefore, limiting the claimed invention to a method of treatment via intranasal administration or intraperitoneal injection with at least 1 x 105 PFU/mouse of the CMV vector comprising FST344 or hTERT.
The State of the Prior Art, The Level of One of Ordinary Skill and The Level of Predictability in the Art
Reliance on animal models is not predictive of clinical outcome. This has been complicated by the inability to extrapolate delivery methods in animals with those in humans or higher animals.
Mingozzi and High (Immune responses to AAV vectors: overcoming barriers to successful gene therapy, Blood 122(1): 23-36, 2013) demonstrate that the human findings are not recapitulated from the animal studies (page 26, col 2, “it seemed logical that one could model the human immune response in these animals, but multiple attempts to do so have also failed”). Hence, lessons learned from small animals such as the mice studies could not recapitulate the ability to deliver adequately in humans.
Kattenhorn et al (Adeno-Associated Virus Gene Therapy for Liver Disease, Human Gene Therapy 27(12): 947-961, November 28, 2016) taught concerns for translation lead to extensive analysis of the effects on clinical use. The use of AAV after initial promising results went on hiatus (pg. 947, col. 2, “clinical hiatus in the field”) as the animal models were deficient (pg. 953, col. 2, “Although animal models predicted many aspects of the human immune response…, they largely failed to predict responses to AAV capsid”; “Work done in nonhuman primates has not met with any additional success”). This emphasizes that the challenge in humans is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. Eventually, the use of AAV is serotype-dependent (e.g. pg. 950, col. 1), organ and concentration dependent. The inability to develop an adequate means of overcoming humoral responses, neutralizing antibody, inactivation of transgene expression, shedding and refractory cells limits the successful means by which the nucleic acid can be administered.
Huang et al (Genetic Manipulation of Brown Fat Via Oral Administration of an Engineered Recombinant Adeno-associated Viral Serotype Vector, Molecular Therapy 24(6): 1062-1069, 2016) is considered relevant prior art for having taught oral administration of rAAV, whereupon transgene expression was not detected in heart, stomach, intestine, skeletal muscle, kidney, spleen, lung, nor brain (e.g. pg. 1062, col. 2; Figure 2).
Tian et al (Aerosol Inhalation-mediated Delivery of an Adeno-associated Virus 5-expressed Antagonistic Interleukin-4 Mutant Ameliorates Experimental Murine Asthma, Archives of Medical Research 50: 384-392, 2019) is considered relevant art for having taught inhaled administration of rAAV, whereupon AAV vector DNA was detected in the lung, but not detected in other organs, such as heart, liver, kidney, brain, lymph nodes, and gonads (e.g. Abstract; pg. 386, col. 2).
Post filing art of Tsaregorodtseva et al. (Int. J. Mol. Sci. 2025, 26, 5224) discloses viral vector gene therapy with different viral vector types including Adeno-Associate Viruses, Lentiviruses, Retrovirus, Adenoviruses, Herpes Simplex Viruses ( page 11 Table 2 ) is unpredictable due to the generation of neutralizing antibodies that can reduce delivery and expression efficacy. Thus, these viral vectors have limitations for gene therapy in human subject.
The Quantity of Any Necessary Experimentation to Make or Use the Invention
Thus, the quantity of necessary experimentation to make or use the invention as claimed, based upon what is known in the art and what has been disclosed in the specification, will create an undue burden for a person of ordinary skill in the art to demonstrate that the broadly claimed genus of CMV vectors and broadly claimed dosage may be administered by the broadly encompassed administration routes so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result treating age related diseases.
It is generally recognized in the art that biological compounds often react unpredictably under different circumstances (Nationwide Chem. Corp. v. Wright, 458 F. supp. 828, 839, 192 USPQ95, 105(M.D. Fla. 1976); Affd 584 F.2d 714, 200 USPQ257 (5th Cir. 1978); In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970)). The relative skill of the artisan and the unpredictability of the pharmaceutical art are very high. Where the physiological activity of a chemical or biological compound is considered to be an unpredictable art (Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved" (See In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970))), the skilled artisan would have not known how to extrapolate the results provided in the instant specification.
The gene therapy art is extremely unpredictable. The unpredictability is manifested in the poor and unpredictable targeting of the gene therapy vectors to target cells (the enormous genus of possible AAV serotypes disclosed), routes of administration (as disclosed, do not even require direct administration to the diseased tissue), the transient and unpredictable expression of the transgenes in target cells (the genus of disclosed possible promoters and/or regulatory sequences), and the unsuitability of many animal models of human diseases, etc.…, all critical for the success of a gene therapy method.
As In re Gardner, Roe and Willey, 427 F.2d 786,789 (C.C.P.A. 1970), the skilled artisan might eventually find out how to use the invention after “a great deal of work”. In the case of In re Gardner, Roe and Willey, the invention was a compound which the inventor claimed to have antidepressant activity, but was not enabled because the inventor failed to disclose how to use the invention based on insufficient disclosure of effective drug dosage. The court held that “the law requires that the disclosure in the application shall inform them how to use, not how to find out how to use for themselves”.
Perrin (Make Mouse Studies Work, Nature (507): 423-425, 2014) taught that the series of clinical trials for a potential therapy can cost hundreds of millions of dollars. The human costs are even greater (pg. 423, col. 1). For example, while 12 clinical trials were tested for the treatment of ALS, all but one failed in the clinic (pg. 423, col. 2). Experiments necessary in preclinical animal models to characterize new drugs or therapeutic compounds are expensive, time-consuming, and will not, in themselves, lead to new treatments. But without this upfront investment, financial resources for clinical trials are being wasted and [human] lives are being lost (pg. 424, col. 1). Patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment. Clinical trials typically require patients to commit to year or more of treatment, during which they are precluded from pursuing other experimental options (pg. 423, col.2 1-3).
Greenberg (Gene Therapy for heart failure, Trends in Cardiovascular Medicine 27: 216-222, 2017) is considered relevant prior art for taught that despite success in experimental animal models, translating gene transfer strategies from the laboratory to the clinic remains at an early stage (Abstract). The success of gene therapy depends on a variety of factors that will ultimately determine the level of transgene expression within the targeted cells. These factors include the vector used for delivery, the method and conditions of delivery of the vector to the [target tissue], the dose that is given and interactions between the host and the vector that alter the efficiency of transfection of [target] cells (e.g. pg. 217, col. 1). Failure of therapeutic results may arise because the vector DNA levels were at the lower end of the threshold for dose-response curves in pharmacology studies, and/or only a small proportion of target cells were expressing the therapeutic transgene (e.g. pg. 220, col. 1). Although the use of AAVs for gene therapy is appealing, additional information about the best strain of AAVs to use in human patients is needed. Experience indicates that there is a need to carefully consider the dose of the gene therapy vector; however, this has proved to be difficult in early phase developmental studies due to the complexity and cost of such studies (e.g. pg. 221, col. 1).
Maguire et al (Viral vectors for gene delivery to the inner ear, Hearing Research 394: e107927, 13 pages, doi.org/10.1016/j.heares.2020.107927, 2020) is considered relevant post-filing art for taught that despite the progress with AAV vectors in the inner ear, little is known regarding the mechanism of transduction of specific cells by AAV within the cochlea (e.g. pg. 2, col. 2). There are limitations to what experiments in mice can tell us about the true translation potential of a new therapeutic (e.g. pg. 8, col. 2), e.g. species-related physiological differences between mice and humans (e.g. pg. 9, col. 1). The AAV dosage is a significant factor in achieving transduction of the target cell, as insufficient dosage may achieve no transduction of the target cells (e.g. pg. 9, col. 2).
In conclusion, the specification fails to provide any guidance as to how an artisan would have dealt with the art-recognized limitations of the claimed method commensurate with the scope of the claimed invention and therefore, limiting the claimed invention to a treatment reducing hair loss in mice, increasing number of mitochondria, increased telomere, increased glucose intolerance, length and resistance in body weight loss via the administration of a CMV viral vector comprising FS344 and/or hTERT at a dosage of 1 x 105 PFU/mouse is proper. The specification contemplates a recombinant CMV vector system capable of delivering one or more therapeutic genes (e.g., hTERT, hFST, KLOTHO, Dsup, PGC1α) to a wide range of tissues, wherein vectors are constructed using BAC engineering, allowing for large or multiple gene inserts. These vectors are contemplated as being able to be administered intranasally or by injection, resulting in widespread, long-lasting gene expression and physiological benefits (increased longevity, muscle mass, metabolic health, hair retention) without carcinogenicity (paragraph [0056] of the published application) . The system is designed for both human and animal use. However, the specification is silent about any method of directly administering the claimed CMV vector to a human subject to provide one or more of increased glucose tolerance, decreased glycosylated hemoglobin, increased physical coordination, increased telomere length, reduced age-related hair loss, increased resistance to loss in body weight, increased life span, increased mitochondria in skeletal muscle, increased mitochondria in heart muscle, or an increase in markers of autophagy (claims 14 and 41).Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
In response to Applicant’s arguments regarding the 112a Enablement rejection,
Applicant’s arguments and amendments have been considered. Arguments regarding the genes as well as the specific effects of the therapy are persuasive in light of the amendments made, however the arguments regarding dosage and its correlation to the species of subject are not persuasive.
Applicant argues that significant animal model data enables the claimed methods beyond the animal model itself and that in order to test treatment on humans would require Phase II clinical trials which has been determined to not be necessary and left to the FDA.
Examiner disagrees. In particular, there is undue experimentation in translating the mouse model to human subject. This is from the only dosage disclosed being in units of PFU/mouse. One cannot determine PFU/mouse in a human subject as a unit of measurement. In fact, Applicants have provided Post filing art of Tsaregorodtseva et al. (Int. J. Mol. Sci. 2025, 26, 5224) highlighting the unpredictability of gene therapy with different viral vector types including Adeno-Associate Viruses, Lentiviruses, Retrovirus, Adenoviruses, Herpes Simplex Viruses ( page 11 Table 2 ) is unpredictable due to the generation of neutralizing antibodies that can reduce delivery and expression efficacy. The Specification as filed does not provide evidence of any in vivo human therapy using the claimed CMV vectors and resulting the one or more claimed properties. There is no disclosure of potential dosages of PFU/human nor any dosage that is based on the weight of the subject which could be more easily translatable. The above enablement rejections provide evidence for the issues in translating mouse models to that of human subjects in clinical trials and the costs that come with doing so.
Claim Rejections - 35 USC § 103
Claims 14, 21, 24-25, 32 remain rejected, and 37-44 are newly rejected under 35 U.S.C. 103 as being unpatentable over Mendell (Molecular Therapy Vol. 25 No 4 April 2017) in view of Mendez (Medical Microbiology and Immunology (2019) 208:349–363; previously cited) and Bongard (PLoS Pathog 15(9): e1008043).
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 08/19/2025.
Regarding claims 14, 32, 41 and 44, Mendell teaches a method for treating sporadic inclusion body myositis which affects subjects most commonly after the age of 50 (i.e. age-related disease) (Abstract, p. 870, 1st column). Human subjects 50 years of age or older at the time of disease onset were injected directly with a recombinant rAAV1 vector comprising contains the cytomegalovirus (CMV) immediate early promoter/Enhancer and human follistatin 344 (FS344) for gene transfer (i.e. injectable delivery) (p. 871, 1st column).
However, Mendell does not teach administration of FS344 in a CMV viral vector and cloning of additional genes such as FST.
Mendez teaches that human cytomegalovirus (HCMV) has desirable qualities in developing vectors such as a large genome of CMVs allowing the insertion of multiple foreign genes, since more than 50 kb can be removed from human CMV (HCMV) without affecting virus replication (p. 350, 1st paragraph). Additionally, CMV vectors can persist lifelong within their host and are a safer alternative due to the oncogenic potential of lentiviruses (p. 350, 2nd paragraph).
Based on such teachings, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date to utilize a human recombinant CMV viral vector as taught by Mendez in order to express the FS344 gene in vivo with a reasonable expectation of success. Mendez teaches that human CMV viral vectors have desirable qualities such as allowing insertion of multiple foreign genes and are a safer alternative to other known viral vectors (p. 350, 1st-2nd paragraph). Therefore, the anti-aging genes could be easily cloned and expressed by the human recombinant CMV viral vector when administered to a subject or cell since Mendez discloses that CMV can accommodate large inserts. Regarding the limitation of very gene being fused to a separate native CMV gene with a separate promoter and reading frame, this separation can be at once envisaged within the claimed vector. See MPEP 2131.02.
However, Mendell and Mendez do not teach that the CMV vector is administered at a dosage of at least 1 x 105 PFU.
Bongard teaches that it is known in the art to administer CMV vectors at a dosage of 2 x 105 PFU though intraperitoneal injection to express transgenes in mice (p. 5, 1st paragraph; p. 23, 3rd and 5th paragraphs).
Based on such teachings, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date to administer the CMV viral vector as taught by Mendell and Mendez at a dosage of 2 x 105 PFU as taught by Bongard in order to express the FS344 gene and additional cloned genes in vivo with a reasonable expectation of success. As discussed above, Bongard teaches that effective expression of transgenes in a CMV vector is present at 2 x 105 PFU in a mouse subject.
Regarding the limitations of “wherein the recombinant CMV viral vector provides the subject one or more of increased glucose tolerance, decreased glycosylated hemoglobin, increased telomere length, reduced age- related hair loss, increased resistance to loss in body weight, increased mitochondria in skeletal muscle, increased mitochondria in heart muscle, or an increase in markers of autophagy,” as each and every method step and limitation is rendered obvious by the combination of Mendell, Mendez and Bongard, the same method steps would yield the same predictable results with a reasonable expectation of success.
Regarding claim 24 and 25, the combined teachings of Mendell, Mendez and Bongard render obvious claim 14. Moreover, Mendell states that the intermediate early promoter/enhancer of CMV is utilized (p. 875, 1st paragraph). Therefore, it is interpreted that the IE1 gene is utilized and therefore the gene is fused to said native CMV gene.
Regarding claims 37-38, the combined teachings of Mendell, Mendez and Bongard render obvious claim 14. As each and every method step and claimed dosage is taught by the combination, the same method steps would yield the same predictable results with a reasonable expectation of success. Thus, an artisan would expect the serum levels and mRNA increase to be the same.
Regarding claims 39, 40, 42 and 43, the combined teachings of Mendell, Mendez and Bongard render obvious claim 14 and claim 41. Moreover, Mendell teaches administering the viral vector to human subjects (p. 871, 1st column), and Bongard teaches administering the viral vector to mice (p. 5, 1st paragraph).
Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
In response to Applicant’s arguments and amendments regarding the 103 rejection over Mendell and Mendez,
Applicant’s arguments and amendments which provide new limitations such as dosage have necessitated a new grounds of rejection. The maintained rejection has been modified by Bongard to address the limitations.
In response to applicant's argument that Mendez contemplates vaccine vectors and not gene therapy vectors, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Examiner has previously stated that by Applicant’s own admission, the faults of the CMV vectors make them promising candidates for gene therapy (Remarks filed 10/24/2024, p. 8, 2nd paragraph), therefore an artisan would have been motivated to utilize such a vector for the inclusion of additional genes such as hTERT, hFST, KLOTHO, Dsup, PGC1α and others and this would not teach away from utilizing CMV vectors in gene therapy. Upon responding to this, Applicant argues impermissible hindsight in citing findings in arguments. Examiner merely is utilizing the arguments to underscore a point. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). The rejection is not merely based on Applicant’s disclosure. The rejection is based on the properties that would lead one of ordinary skill to modify Mendell with Mendez’s concept due to advantageous properties. While Applicant argues that their intended use is different, this does not teach away when considering their advantageous properties outlined in the rejection. In relation to Applicants’ arguments that “While a strong induction of cytotoxic T cells is beneficial in the context of a vaccine, cytotoxicity against transduced cells can significantly limit the effectiveness of gene therapy” (page 10 of Applicants’ remarks, last paragraph), it is noted that to be given substantial weight in the determination of obviousness or nonobviousness, evidence of secondary considerations must be relevant to the subject matter as claimed, and therefore the examiner must determine whether there is a nexus between the merits of the claimed invention and the evidence of secondary considerations. Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d 281, 305 n.42, 227 USPQ 657, 673-674 n. 42 (Fed. Cir. 1985). The term “nexus” designates a factually and legally sufficient connection between the objective evidence of nonobviousness and the claimed invention so that the evidence is of probative value in the determination of nonobviousness. Demaco Corp. v. F. Von Langsdorff Licensing Ltd., 851 F.2d 1387, 7 USPQ2d 1222 (Fed. Cir. 1988). See M.P.E.P. § 716.01(b).
Furthermore, Applicants’ opinion is unsupported by any specific or real evidence, while the options of the skill in the art are given respectful consideration, in the absence of any actual evidence of “unexpected results”, the opinions of the inventor do not overcome a case of prima facie obviousness. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). See MPEP § 716.01(c) for examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration.
In this case, Applicants have provided post filing art of Tsaregorodtseva et al. (Int. J. Mol. Sci. 2025, 26, 5224) highlighting the unpredictability of gene therapy in relation to formation of nAbs against AAV vectors based on crossreactivity to different wild-type AAV serotypes (page 3, para 1), activation of immune responses to the gene themselves (“therapeutic genes themselves can trigger immune responses that significantly impact their efficacy and safety”) (page 7, para 3), induction of Abs based on prior exposure to a similar virus or gene (page 7, para 8; page 8, para. 5), initial response relative to repeated administration of viral vectors (page 2, para 2) among others. Thus, in contrast to Applicant’s remarks, the nature of raising neutralizing antibodies that could significantly limit the effectiveness of gene therapy of transduced cells is a complex process that would not teach away from . Mendell's intended purpose of reduced fibrosis after follistatin gene therapy. Furthermore, Applicant’s argument that the “suggestion of prior art” would not have lead someone to utilize the CMV vector in Mendell’s method and teaches away is not persuasive. Again, it is reiterated that there is a suggestion in CMV’s advantageous properties in gene therapy.
Claims 21 and 29 is rejected under 35 U.S.C. 103 as being unpatentable over Mendell (supra) in view of Mendez (supra) and Bongard (supra) as applied to claim 14 above, and in further view of Brodie (WO2018211510A1; previously cited).
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 08/19/2025.
As discussed above Mendell, Mendez, and Bongard provide teachings which make obvious treating conditions associated with anti-aging through injection of recombinant CMV viral vectors wherein the CMV vectors are introduced to express FS344 genes as iterated above in the 103 rejection the content of which is incorporated herein, in its entirety.
However, these references do not teach that additionally Klotho is introduced via the viral vector.
Brodie teaches vectors which can be a viral vector such as adenoviral vectors and herpes viral vectors encoding multiple anti-aging genes such as Klotho (KL), TIMP2, and GDF11 which are administered to cells so that they express the anti-aging factor in a method of treating conditions related to anti-ageing (para. 0086, 0091, 0096).
Based on such teachings, it would be obvious to one of ordinary skill in the art to additionally include Klotho as taught by Brodie in the viral vector comprising FS344 with a reasonable expectation of success. An artisan would be motivated to administer Klotho as well as FS344 as Klotho is known to be an anti-aging gene and utilized in viral vectors to treat conditions associated with aging which are administered to subjects (para. 0086, 0091, 0096).
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Claim 22, 30 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Mendell (supra) in view of Mendez (supra), Bongard (supra) and Brodie (supra) as applied to claims 14 and 21 above and in further view of de Jesus (EMBO Mol Med. 2012 Aug; 4(8): 691–704; previously cited) and Podlevsky (Nucleic Acids Research, 2008, Vol. 36, Database issue D339–D343; previously cited).
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 08/19/2025.
As discussed in the above 103 rejection, Mendell, Mendez, Bongard and Brodie teach a method of treatment via direct injectable administration of CMV viral vectors comprising FS344 and Klotho as iterated above in the 103 rejection the content of which is incorporated herein, in its entirety.
However, Mendell, Mendez, Bongard and Brodie do not teach that TERT is utilized within the CMV vector.
De Jesus teaches an AAV vector encoding murine TERT with a CMV promoter which resulted in delays in ageing in mice, increasing median and maximum longevity (p. 692, 2nd column, Figure 3).
Based on such teachings, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date to express TERT in addition to the anti-aging FS344 gene and Klotho within the vector of Mendell, Mendez, Bongard and Brodie in vivo with a reasonable expectation of success. An artisan would have been motivated to not only utilize the vector to express FS344 in Mendell, but also substitute TERT for FS344 in a method of inhibiting aging and treating age related conditions as TERT is known in the art to increase the median and maximum longevity in mice treated with an AAV-TERT vector (De Jesus; Figure 3).
However, in regard to claim 22, these references do not teach that the TERT is human TERT (hTERT). De Jesus provides teachings for murine TERT (mTERT).
Podlevsky teaches that amino acid sequences of TERT are relatively conserved across all eukaryotes and vertebrates (p. D341, Alignments, Figure 1).
Based on such teachings, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date to express hTERT instead of mTERT in the vector with a reasonable expectation of success. As Podlevsky teaches that amino acid sequences of TERT are relatively conserved across vertebrates, an artisan would find substituting hTERT in place of mTERT to be substituting known alternative species of TERT. De Jesus additionally teaches that the accumulation of short/damaged telomeres with increasing age is considering on of the main sources of aging associated DNA damage in both humans and mice (p. 697, last paragraph). In light of this, an artisan would be motivated to utilize human TERT to model human disease via the same mouse means of de Jesus.
Regarding claim 33, the combination of Mendell, Mendez, Bongard and Brodie render obvious claim 14 and 24. The references do not teach wherein the one or more exogenous donor gene is fused to a separate CMV gene, with a separate promote and in a separate open reading frame.
It would have been obvious to one of ordinary skill in the art to do so as it would be duplicating how the expression of one gene within the CMV viral vector is expressed. Therefore, an artisan would express a second gene in the same construct in the same manner.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Claim 26-28 is rejected under 35 U.S.C. 103 as being unpatentable over Mendell (supra) in view of Mendez (supra) and Bongard (supra) as applied to claim 14 above, and in further view of Liu (Scientific Reports 7: 2193; previously cited).
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 08/19/2025.
As discussed above Mendell, Mendez and Bongard provide teachings which make obvious treating conditions associated with anti-aging via the administration of CMV viral vectors through injection wherein the CMV vectors are introduced to express FST genes wherein one or more of the genes are linked the native CMV as iterated above in the 103 rejection the content of which is incorporated herein, in its entirety.
However, regarding claim 26-28, these references do not teach wherein one or more genes are fused to a native CMV gene via a sequence coding for a 2A self-cleaving peptide such as P2A.
Liu teaches that self-cleaving peptides such as P2A have been shown in studies to have high efficiency when utilized in polycistronic vectors (p. 2, 1st paragraph).
Based on such teachings, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date to fuse the genes of interest via a P2A self-cleaving peptide in the CMV viral vector with a reasonable expectation of success. As Liu teaches that self-cleaving peptides specifically ones such as P2A have been shown in studies to have high efficiency in vectors with more than one gene (p. 2, 1st paragraph).
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Double Patenting
Claims 14, 21-22, 24-30, 32-33 and 37-44 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3, 5, 7, 10 and 27 of copending Application No. 17/680,708 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other.
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 08/19/2025.
Regarding independent claims 14 and 41, ‘708 teaches a method for gene therapy via administering a genetically modified viral vectors comprising one or more donor genes wherein the viral vector is a human cytomegalovirus (CMV) wherein the genes are TERT and FS344 (Claim 1, 10, 20). This is a genus for the species of the present application directed towards a gene therapy method. ‘708 teaches that the vectors is administered intranasally or by injection (Claims 2 and 3).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 14, 21-22, 24-30, 32-33 and 37-44 rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 3 of U.S. Patent No. 11,266,721 in view of Mendez (Medical Microbiology and Immunology (2019) 208:349–363).
Although the claims at issue are not identical, they are not patentably distinct from each other.
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 08/19/2025.
Regarding independent claims 14 and 41, Patent ‘721 teaches a method comprising administering via injection a therapeutically effective amount of hTERT gene and Follistatin-344 gene via a viral vector (Claim 1, 3). Patent ‘721 teaches that the vectors are administered by injection (Claim 3).
However, Patent ‘721 does not teach that the vector is a hCMV vector.
Mendez teaches that human cytomegalovirus (HCMV) has desirable qualities in developing vectors such as a large genome of CMVs allowing the insertion of multiple foreign genes, since more than 50 kb can be removed from human CMV (HCMV) without affecting virus replication (p. 350, 1st paragraph). Additionally, CMV vectors can persist lifelong within their host and are a safer alternative due to the oncogenic potential of lentiviruses (p. 350, 2nd paragraph).
Based on such teachings, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date to utilize a human recombinant CMV viral vector as taught by Mendez in place of the vector taught by Patent ‘721 with a reasonable expectation of success. Mendez teaches that human CMV viral vectors have desirable qualities such as allowing insertion of multiple foreign genes and are a safer alternative to other known viral vectors (p. 350, 1st-2nd paragraph). The limitations of Claim 36 reciting particular therapeutic outcomes are inherent to the viral vector itself and therefore does not add structure.
Therefore the invention is rejected on the grounds of double patenting.
In response to Applicant’s arguments against the Double Patenting Rejections,
As the arguments against double patenting are based on Mendez, (“each of these double patenting rejections rely on Mendez,”), they are also found to be non-persuasive and all double patenting rejections have been modified to address newly recited claims.
New grounds of objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112 (b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 14, 21, 37, 38, and 44 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 14, 21, 37, 38 and 44 have “and/or” conjunctions. This renders the metes and bounds indefinite as it is unclear whether the options are in the alternative or both are required in the claims. For instance, in claim 37, would the same amount of vector administered result in both the telomerase and follistatin serum level or would only one be effected as claimed.
Appropriate correction is required.
Conclusion
No claims are allowed.
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 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.
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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634