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 .
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 9 and 18 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 9 and 18 recite “STP705”, which is the formulation recited in amended claim 1 and therefore does not further limit the base claim. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 11, 12, and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 11 has been amended to require that the patient suffers from “metabolic disruption of adipose tissue”.
The specification does not adequately describe what is specifically required for metabolic disruption of adipose tissue and therefore one would not be able to readily recognize which patients are necessarily included or excluded from the recited genus.
Without further description of the genus, one would not be able to readily envision what type of criteria is required for the organ’s ability to maintain homeostasis to be impaired. For example, chronic stress, inflammation, or metabolic dysregulation are known to overwhelm adipose tissue’s adaptive capacity, as taught by Matar et al. (Frontiers in Endocrinology, 16, 1592683, 2025, 1-33), so would any patient under chronic stress meet the instant limitation of suffering from metabolic disruption of adipose tissue?
Claims 1-6, 9-12, 17, and 18 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 method of inhibiting TGF-β1 and Cox2 with the instantly recited siRNAs, does not reasonably provide enablement for a method of remodeling any type of adipose tissue via any mode of delivery of the instantly recited siRNAs. 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 commensurate in scope with these claims.
Factors to be considered in a determination of lack of enablement 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.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The claims are directed to a method of remodeling any type of adipose tissue via any mode of delivery of the instantly recited composition.
The specification demonstrates delivery of STP705 (the instantly recited siRNAs of claim 1) directly into squamous cell carcinoma tumors at the highest dose (120 µg) exhibited skin changes consistent with panniculitis, an inflammation of subcutaneous adipose tissue.
Direct intratumoral delivery of STP705 at a specific concentration with a result of skin changes consistent with panniculitis, an inflammation of subcutaneous adipose tissue is not enabling for a method of remodeling any type of adipose tissue via any mode of delivery in any possible patient of STP705.
Instant claim 11 has been amended to require for the patient to suffer from metabolic disruption of adipose tissue. The specification does not draw an adequate nexus between panniculitis and treating any patient with any metabolic disruption of adipose tissue.
Additionally, there is no guidance in the specification as filed that teaches how to deliver the instantly recited siRNAs and predictably remodel adipose tissue in vivo.
Although applicant has demonstrated RNA interference in vitro via the instantly recited siRNAs, applicant is not enabled for mediating RNA interference in vivo by the broadly recited methods, as delivery and effective action therein is known in the art to be unpredictable with regards to dsRNA duplexes. Activity in vitro is not predictable of the in vivo therapeutic effect in the in vivo complex environment.
Fujita et al. (Int. J. Mol. Sci. 2015, 16, 5254-5270) teach that two types of small RNA molecules, small interfering RNAs (siRNAs) and microRNAs (miRNAs), have a central function in RNAi technology. The success of RNAi-based therapeutic delivery may be dependent upon uncovering a delivery route, sophisticated delivery carriers, and nucleic acid modifications (page 5254). Fujita et al. teach that the success of an RNAi-based therapy in clinical trials rests on careful selection of target genes and miRNAs. Moreover, we suggest that a delivery route, sophisticated delivery carriers, chemical modification, and modified RNAi platforms are needed to enhance RNAi effects in cancer cells (pages 5262-5263).
Friedrich et al. (BioDrugs (2022) 36:549–571) teach that still, the development of siRNA therapeutics faces several challenges and issues, including the definition of optimal siRNAs in terms of target, sequence, and chemical modifications, siRNA delivery to its intended site of action, and the absence of unspecific off-target effects (Abstract). Friedrich et al. teach that the use of short siRNA is preferred because longer siRNAs can provoke an inflammatory antiviral immune response (page 551).
As outlined above, it is well known that there is a high level of unpredictability in the RNAi art for therapeutic in vivo applications and design. The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention, namely a broad method of remodeling any possible adipose tissue via broad systemic delivery of the instant composition encompassing in vivo effects.
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether introduction of the instantly recited composition in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful remodeling of any type of adipose tissue. To practice the claimed invention, one of skill in the art would have to de novo determine; the stability of the molecule in vivo, delivery of the molecule to the whole organism, specificity to the target tissue in vivo, dosage and toxicity in vivo, and entry of the molecule into the cell in vivo and the effective action therein. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
Response to Arguments
Applicant argues that applicant has amended claims 1 and 11 to recite specific siRNA molecules, and the use of these molecules is clearly described throughout the specification. The specification provides the skilled worker with extensive experimental detail with respect to the siRNA molecules recited in the claims and the claims are fully enabled.
As set forth above, direct intratumoral delivery of STP705 at a specific concentration with a result of skin changes consistent with panniculitis, an inflammation of subcutaneous adipose tissue is not enabling for a method of remodeling any type of adipose tissue via any mode of delivery in any possible patient of STP705.
Instant claim 11 has been amended to require for the patient to suffer from metabolic disruption of adipose tissue. The specification does not draw an adequate nexus between panniculitis and treating any patient with any metabolic disruption of adipose tissue.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-6, 9, 10, and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over He et al. (US 2012/0115923 A1), in view of Leng et al. (Molecular Therapy, vol. 20, no. 12, 2012, 2282-2290), and Lu et al. (US 2010/0319074 A1).
He et al. teach compositions and methods using siRNA to target various genes expressed in cells of injured tissue during scar formation to promote scar-free wound healing (abstract).
He et al. teach: [0014] The composition used for contacting injured tissues or cells may comprise a plurality of targeting polynucleotides of the invention and the polynucleotides may target a plurality of gene sequences. The composition may further comprise a TargeTran nanoparticle solution. The targeting polynucleotides found in the composition may target sequences of genes such as Cox-2 and TGF-β, found in tables 1-7. The targeting polynucleotides may comprise one or more siRNA duplexes against one or more gene sequences, such as Cox-2/ TGF-β1/IL-8, Cox-2/ TGF-β1/IL-6, Cox-2/ TGF-β1/fibronectin, Cox-2/ TGF-β1/smad3 and other combinations of three or more gene sequences. The polynucleotides of the invention may be mixed in equal or different ratios (instant claim 1).
He et al. teaches a pharmaceutical composition comprising the nanoparticle formulation comprising the siRNAs and a pharmaceutically acceptable carrier [0045] (instant claim 1).
He et al. teach incorporation of carriers including cationic copolypeptides such as histidine-lysine (HK) ([0051] and claims) (instant claims 2, 3, and 12). He et al. teaches that the siRNA can be conjugated (RGD-PEG-PEI)([0051]).
He et al. teach: [0046] A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral, nasal, inhalation, transdermal (topical), transmucosal, and rectal administration (instant claims 5 and 6).
He et al. teach: [0021] Efficient silencing is generally observed with siRNA duplexes composed of a 16-30 nt sense strand and a 16-30 nt antisense strand of the same length.
He et al. teach: [0013] This invention also provides a method of suppressing scar formation during the cutaneous wound healing process by contacting the injured tissues or cells, at a time of a surgery, wound treatment, injury recovery or skin grafting, with a composition comprising a targeting polynucleotide of the invention. In one embodiment, the composition is applied topically. In another embodiment, the composition is locally injected.
Since He et al. teaches a method comprising each of the instant method steps, the method would necessarily achieve the recited outcome of remodeling adipose tissue, absent evidence to the contrary (instant claims 1 and 10). The only recited method step is delivering of the siRNAs.
He et al. does not teach that the copolymer is H3K4b (instant claim 4).
However, it would have been obvious for the copolymer to be H3K4b because Leng et al. teach that H3K4b siRNA carriers have greater pH buffering capacity comparted with other HK peptides and that there carriers minimize toxicity (abstract). One would reasonably expect the benefits taught by Leng et al. when incorporated into the formulation of He et al.
He et al. does not teach the specific siRNA sequences of STP705 (instant SEQ ID NOs: 1-4) as the Cox-2 and TGF-β siRNAs (instant claims 9 and 18).
However, it would have been obvious to select these sequences as a matter of design choice because they were known Cox-2 and TGF-β1 siRNAs, both taught by Lu et al. for healing and skin conditions (see the 5th 25-mer sense sequence for Cox-2, page 15; and see the 1st sense sequence for TGF-β1, page 14).
Response to Arguments
Applicant argues that nothing in He teaches or suggests that siRNAs targeting TGF-β1 and COX-2 can be used to remodel adipose tissue.
The instant method steps are obvious in view of the cited references. The claims do not require any specific patient population and the preamble is not a method step. The intended use of the preamble would necessarily flow from the method steps or the method is not enabled. The claims are directed to broad systemic delivery of the instant composition in any patient, which is obvious in view of the cited references.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
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