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 .
DETAILED ACTION
Applicant’s amendments and remarks filed on May 7, 2026 are acknowledged. Claims 2-4, 10, 12-17, and 19-31 have been canceled. Claims 1, 8, 11, and 18 were amended. Claims 1, 5-9, 11, 18, and 32-35 are pending and are examined on the merits herein.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 May 7, 2026 has been entered.
Priority
This application claims priority to PCT/US2020/052856 filed on September 25, 2020 which claims priority to U.S. provisional application 62/905,694 filed on September 25, 2019.
Withdrawn Objections
In view of Applicant’s amendments and response, the objections to the specification are withdrawn.
In view of Applicant’s amendments and response, the objection to claim 8 is withdrawn.
Withdrawn Rejections
In view of Applicant’s amendments and response, the 35 U.S.C 112(b) rejection is withdrawn.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 5-9, 11, 18, and 32-35 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
There are many factors to be considered when determining whether there is
sufficient evidence to support a determination that a disclosure does not satisfy the
enablement requirement and whether any necessary experimentation is "undue".
These factors include, but are not limited to: (A) The breadth of the claims; (B) The
nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary
skill; (E) The level of predictability in the art; (F) The amount of direction provided by the
inventor; (G) The existence of working examples; and (H) The quantity of
experimentation needed to make or use the invention based on the content of the
disclosure. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Breadth of claims and nature of the invention:
Claims 1, 5-9, 11, 18, and 32 are drawn to a method of reducing Rlim in a mammalian subject comprising administering an siRNA targeting Rlim to a mammalian subject in need thereof wherein the siRNA comprises at least 10 consecutive nucleotides of SEQ ID NO: 28, 36, 38, 40, 42, 44, or 46.
Claims 33 and 34 are drawn to a method of preventing diet-induced obesity in a mammalian subject comprising administering a therapeutically effective amount of an siRNA targeting Rlim to the mammalian subject wherein the siRNA comprises at least 10 consecutive nucleotides of SEQ ID NO: 28, 36, 38, 40, 42, 44, or 46.
Claim 35 is drawn to a method of preventing liver steatosis in a mammalian subject comprising administering a therapeutically effective amount of an siRNA targeting Rlim to the mammalian subject wherein the siRNA comprises at least 10 consecutive nucleotides of SEQ ID NO: 28, 36, 38, 40, 42, 44, or 46.
Amount of direction provided by the inventor and existence of working
examples:
The instant specification as filed envisions the following:
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[page 2, last two paragraphs]. Further, the specification envisions in some embodiments the disorder is diet-induced obesity (e.g., high-calorie or high-fat diet induced obesity) [page 11, second full paragraph]. The specification envisions that the methods include administering one or more inhibitory nucleic acids targeting Rlim wherein the inhibitory nucleic acids include antisense oligonucleotides, ribozymes, siRNA compounds, single or double-stranded RNA interference (RNAi) compounds such as siRNA compounds, modified bases/locked nucleic acids (LNAs), peptide nucleic acids (PNAs), and other oligomeric compounds or oligonucleotide mimetics that hybridize to at least a portion of the target Rlim nucleic acid [page 13, last paragraph bridging to page 14].
The specification discloses in Example 1 that twelve chemically modified siRNAs of Rlim sequences conserved between mouse and human were screened and seven were identified as efficiently knocking down Rlim in N2A cells. The use of the chemically modified siRNAs will allow modification of Rlim activity in vivo thereby influencing food intake and ultimately body weight [page 46, first full paragraph]. Furthermore, the specification discloses that siRNA-mediated silencing of Rlim in mice was used to examine whether the interference of Rlim in the brain causes the observed phenotype and to provide evidence that interference with the Rlim pathway protects from obesity. Specifically, to silence endogenous Rlim in the CNS of mice wild-type for Rlim, chemically modified siRNAs with a divalent chemical scaffold were injected into the 3rd ventricle in the brain [page 49, first full paragraph]. The specification discloses that mice lacking Rlim were protected from obesity induced by either HFD, age or change of temperature and demonstrated that the RlimKO mouse model is relevant to human obesity and associated pathologies [page 44, last paragraph bridging to page 45]. However, the working example does not provide evidence that the siRNAs targeting Rlim are capable of preventing diet-induced obesity or preventing liver steatosis.
State of the prior art, level of predictability in the art, and level of one of
ordinary skill:
A review of the prior art shows that the state of the art of administering an
siRNA targeting Rlim to prevent diet-induced obesity or prevent liver steatosis is immature and nascent.
Petzke et al. (International Journal of Molecular Sciences 2014) discloses that high-protein diets have been shown to prevent the development of diet-induced obesity and can improve associated metabolic disorders in mice [abstract]. Petzke et al. also discloses that it is a challenge to find effective treatments and preventive strategies to reduce the extent of overweight [page 1374, first paragraph].
Although post-filing, Portincasa et al. (International Journal of Molecular Sciences 2024) discloses that exercise can reduce hepatic steatosis and improve liver stiffness [207], independently of dietary changes [page 15, second paragraph].
Frints et al. (Molecular Psychiatry 2019; reference previously cited by the Examiner) discloses that the current understanding of the functions of human Rlim is sparse even though its mouse ortholog has been studied in vitro and in vivo [page 1748, right column bridging to page 1749, left column]. Frints et al. demonstrated that loss-of-function mutations result in truncal/central obesity in seven out of thirteen human males studied [page 1757, right column, first full paragraph].
Lai et al. (Nutrition & Diabetes 2014; reference previously cited by the Examiner)
discloses that although many aspects of rodent type 2 diabetes mellitus have been elucidated, correlation to human obesity/diabetes remains poor. Dietary modification in rodents appears to have limited translatable benefit for understanding and treating human obesity and diabetes due—at least in part—to divergent dietary compositions, species/strain and gender variability, inconsistent disease penetrance, severity and duration and lack of resemblance to human obesogenic pathophysiology. Therefore future research efforts dedicated to acquiring translationally relevant data—specifically human data, rather than findings based on rodent studies—would accelerate the understanding of disease mechanisms and development of therapeutics for human obesity/T2DM [abstract].
Although post-filing, Singh et al. (Cells 2021; reference previously cited by the Examiner) teaches that although there are many similarities between mouse and human BAT, notable morphological and anatomical differences also exist. Therefore, in order to translate the significance of rodent studies in humans, it is important to generate proof of concept studies in humans for successful clinical outcomes [page 11, last paragraph]. Singh et al. also teaches that recent studies demonstrating the therapeutic potential of transplanted BAT in rodent studies to improve weight loss and improved insulin sensitivity have not been explored in human subjects. The effectiveness and clinical relevance of BAT activation and recruitment in human subjects needs to be further explored in detail [page 14, first paragraph].
While the state of the art of administering an siRNA targeting Rlim to prevent
diet-induced obesity or prevent liver steatosis is immature and nascent, as evidenced by Lai et al. and Singh et al., there is also limited translatability between mouse models and humans. Thus one of ordinary skill in the art would recognize that inhibiting Rlim expression either through mutations or targeting with an siRNA would have been unpredictable and would not expect to prevent diet-induced obesity or liver steatosis.
Quantity of experimentation:
In view of the breadth of the claims which embrace preventing diet-induced obesity and preventing liver steatosis in a mammalian subject comprising administering a therapeutically effective amount of an siRNA targeting Rlim and the failure to provide adequate guidance to overcome the state and level of predictability of the art, one of skill would have to perform undue experimentation in order to practice the invention commensurate in scope with the claims.
Response to Arguments
Applicant's arguments filed May 7, 2026 have been fully considered but they are not persuasive.
Applicant asserts the following:
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Applicant further asserts the following:
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Applicant also submits as evidence that the examples provided in the specification “correlate” with the presently claimed methods and thus constitute enabling “working examples” to convince one of skill in the art of the asserted utility.
These arguments are not found persuasive. As discussed in the previous 35 U.S.C. 112(a) rejection, a review of the prior art shows that the state of the art of administering an inhibitory nucleic acid targeting Rlim to treat obesity or a disorder associated with obesity is immature and nascent. Therefore, the references were provided to establish the state of the art of treating obesity or a disorder associated with obesity and to provide as evidence that the results obtained from the mouse model used in the instant application does not translate to humans. Although the instant claims are directed to administering a therapeutically effective amount of an siRNA targeting Rlim, the state of the art of administering an siRNA targeting Rlim to prevent diet-induced obesity or prevent liver steatosis is immature and nascent. As previously discussed, Frints et al. taught that the understanding of the functions of human Rlim is sparse even though its mouse ortholog has been studied in vitro and in vivo. Furthermore, Lai et al. taught that the correlation between rodents and human obesity remains poor due to divergent dietary compositions, species/strain and gender variability, inconsistent disease penetrance, severity and duration and lack of resemblance to human obesogenic pathophysiology. Moreover, Singh et al. taught that although there are many similarities between mouse and human BAT, notable morphological and anatomical differences also exist. Therefore, in order to translate the significance of rodent studies in humans, it is important to generate proof of concept studies in humans for successful clinical outcomes. Thus, one would recognize that inhibiting Rlim expression either through mutations or targeting with an siRNA would have been unpredictable and would not expect to prevent diet-induced obesity or liver steatosis.
It is noted that Applicant’s assertions regarding the phrase “a therapeutically effective amount” are found persuasive.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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