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 .
Applicant’s election without traverse of siRNA and R175 in the reply filed on 5/21/25 is acknowledged.
Claim Rejections - 35 USC § 112
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 1, 8, and 14 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.
Claim 1 has been amended to require for the disrupting the association is “such that” the p53 mutant is freed from contact with the PEPD and the p53 mutant participates in killing of the cancer cells.
The specification does not set forth the metes and bounds of the terminology “such that” and therefore the claims are not definite. It is unclear what step is required for the association to be such that the p53 mutant is freed from contact with the PEPD and the p53 mutant participates in killing of the cancer cells.
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, 8, and 14 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.
The claims are directed to a method for inhibiting the growth of cancer, the method comprising administration to cancer cells that express one of the recited p53 mutants that promotes cancer growth of any siRNA that is targeted to any PEPD and disrupts association of the p53 mutant with the PEPD.
The specification does not adequately describe the structure required for the siRNA to be targeted to any location on any PEPD sequence and have the function of disrupting association of the p53 mutant with the PEPD.
The specification discloses that once incorporated into RISC, siRNA facilitate cleavage and degradation of targeted mRNA. Thus, for use in RNAi mediated silencing or downregulation of PEPD expression as described herein, siRNA, shRNA, or miRNA can be used (pages 10-11). This broad statement does not adequately describe the structure required for the siRNA to result in the recited function.
The specification discloses that PEPD (sequence undisclosed) binds to the recited p53 mutants in cells. The specification discloses that intratumoral injection of specific PEPD siRNA (sequences not disclosed in the example, so it is unclear what specific region of what specific PEPD target sequence is targeted by the siRNA) in specific breast cancer tumor types that comprise the instantly recited mutations strongly inhibited tumor growth (page 25). The examples do not specifically disclose which siRNAs were utilized. The specification discloses 4 siRNA single stranded sequences (SEQ ID NOs: 2, 3, 4, and 5) that have specific modification patterns in the sense strand that are identical to sequences in a specific location of a specific PEPD target sequence, which is not representative of the entire claimed genus of siRNAs.
The specification does not adequately describe the structure required between the siRNA and the target sequence in order to result in the recited function and the specification does not disclose the sequences of the siRNAs or the target.
Furthermore, the specification does not adequately describe the structure required for the function for any siRNA targeted to any PEPD to “disrupt an association of a p53 mutant with PEPD”. The minimal species of siRNAs targeting PEPD of the specification are not representative of the entire claimed genus and the specification does not even adequately describe the siRNAs or PEPD of the instant specification (the sequences are not disclosed). Without further description of the structure required for the function, one would not be able to readily recognize which siRNAs targeted to which PEPD sequences function by disrupting any type of association of a p53 mutant with PEPD. The specification does not adequately describe what structure or mechanism is required for the “targeting” of any PEPD.
Claim 1 has been amended to require for the disrupting the association is “such that” the p53 mutant is freed from contact with the PEPD and the p53 mutant participates in killing of the cancer cells.
The specification does not adequately describe what structure is required for the siRNA to result in the disruption of the association of the p53 mutant and PEPD such that the p53 mutant is freed from contact with the PEPD and the p53 mutant “participates” in any manner in killing of the cancer cells.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The claims are rejected under the written description requirement for failing to disclose adequate species to represent the claimed genus, the genus being which cancers express the instant mutations, which agents function as siRNAs targeting PEPD and having the function of disrupting any type of association of a p53 mutant with any PEPD.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
With regards to siRNAs targeting PEPD, it appears that the structure is required to have an antisense strand that is fully complementary to 21-23 nucleotides of a specific target mRNA. For example, Elbashir et al. (The EMBO Journal, Vol. 20, No. 23, pages 6877-6888, 2001) teaches that duplexes of 21-23 nt RNAs are the sequence specific mediators of RNAi and that even single mismatches between the siRNA duplex and the target mRNA abolish interference (abstract and page 6888).
The specification does not adequately describe the genus of siRNAs that would result in the recited functions.
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species within the instant enormous genus that function as claimed. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
Response to Arguments
Applicant argues that the "genus" of RNAi agents is reduced to siRNAs that are targeted to the PEPD mRNA and result in the stated function. The sequence of mRNA encoding PEPD is well known in the art. Representative siRNA sequences are disclosed in the specification and are demonstrated to function as claimed. See for example, paragraphs [0048] and [0050] of the publication of this application.
Contrary to applicant’s arguments, the art does not define PEPD as being a single specific sequence and the claims are not even directed to any species (i.e. human) of PEPD. The claims encompass a method of introducing any siRNA “targeting” any PEPD, as well as encompass any PEPD homolog or allele from any species known or yet to be discovered of PEPD, as well as DNA genomic fragments, spliced variants or fragment that retains PEPD-like activity.
Furthermore, although the specification discloses siRNAs that are specific for a single PEPD sequence, the specification does not describe such agents directed to any other species of PEPD to describe the instantly claimed genus of any PEPD. One of ordinary skill in the art could not make such siRNAs targeted to any PEPD without knowledge of the target sequence and the structural relationship required between the siRNA and the sequence.
Additionally, the specification discloses 4 siRNA single stranded sequences (SEQ ID NOs: 2, 3, 4, and 5) that have specific modification patterns in the sense strand that are identical to sequences in a specific location of a specific PEPD target sequence, which is not representative of the entire claimed genus of siRNAs.
Claims 1, 8, and 14 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 PEPD via delivery of siRNA targeted to PEPD, does not reasonably provide enablement for a method of inhibiting the growth of any cancer that expresses any of the instantly recited p53 mutants that promotes cancer growth with any siRNA that is targeted to any region of any PEPD. 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 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 for inhibiting the growth of cancer, the method comprising administration to cancer cells that express one of the recited p53 mutants that promotes cancer growth of any siRNA that is targeted to any PEPD and disrupts association of the p53 mutant with the PEPD.
The specification does not draw an adequate nexus between delivery via any means of any siRNA “targeted” to any location on any PEPD sequence and have the function of disrupting association of the p53 mutant with the PEPD.
The specification discloses that PEPD (sequence undisclosed) binds to the recited p53 mutants in cells. The specification discloses that intratumoral injection of specific PEPD siRNA (sequences not disclosed in the example, so it is unclear what specific region of what specific PEPD target sequence is targeted by the siRNA) in specific breast cancer tumor types that comprise the instantly recited mutations strongly inhibited tumor growth (page 25). The examples do not specifically disclose which siRNAs were utilized. The specification discloses 4 siRNA single stranded sequences (SEQ ID NOs: 2, 3, 4, and 5) that have specific modification patterns in the sense strand that are identical to sequences in a specific location of a specific PEPD target sequence, which is not commensurate in scope with the instantly recited genus of siRNAs.
Claim 1 has been amended to require for the disrupting the association is “such that” the p53 mutant is freed from contact with the PEPD and the p53 mutant participates in killing of the cancer cells.
The specification does not enable broad systemic delivery of any siRNA targeting any PEPD in any region with a predictable outcome of disruption of the association of the p53 mutant and PEPD such that the p53 mutant is freed from contact with the PEPD and the p53 mutant “participates” in any manner in killing of the cancer cells.
The specification discloses PEPD knockdown by siRNA may induce tumor suppressor activity of a specific p53 mutant, E285A, in BT-474 cells. PEPD knockdown in vitro resulted in marked decrease in nuclear p53 level, which is not commensurate in scope with the instant claims.
PEPD siRNA (undisclosed sequence in the example) strongly inhibited the growth of MDA-MB-231 (p53-R280K) breast cancer tumors (page 26).
Specification is not demonstrative of inhibiting the growth of any possible cancer with each of the recited mutations via delivery of any siRNA targeted to any PEPD sequence.
The specification discloses that PEPD binds to p53wT p53R1755H, p53R248Q, p53R273H, and p53R280K with almost identical affinity (see Fig. 6A).
The specification discloses screening of seven cell lines, including SKBR3 (homozygous p53R175H) HCC70 (homozygous p53R248Q),MDA-MB- 468 (homozygous p53R273H) MDA-MB-231 (homozygous p53R280K) MDA-MB-231 (p53KO),MCF-7 (p53WT), and CAL-51 (p53WT). They are human breast cancer cells, either HER2-positive (SKBR3), estrogen receptor-positive (MCF-7), or triple negative (all remaining cell lines). The specification discloses that all the p53 mutants are overexpressed, compared to p53WT, and p53 is absent in MDA-MB-231-p53KO, but interestingly, PEPD is also overexpressed in cells carrying a p53 mutant and even in MDA-MB-231-p53KO (Figure 6B).
The specification demonstrates intratumoral injection of PEPD siRNA strongly inhibit breast tumor growth with p53 R280K, p53 knockout, and p53 R175H. This is not commensurate in scope with a of inhibiting the growth of any cancer via delivery of any siRNA targeting any region of any PEPD.
Although applicant has demonstrated RNA interference in vitro or RNA interference in vivo via intratumoral injection of PEPD siRNAs, applicant is not enabled for mediating RNA interference in vivo by the broadly recited methods, as delivery is known in the art to be unpredictable with regards to dsRNA duplexes.
The references cited herein illustrate the state of the art for therapeutic in vivo applications using dsRNA.
For example, Elbashir et al. (The EMBO Journal, Vol. 20, No. 23, pages 6877-6888, 2001) teaches that duplexes of 21-23 nt RNAs are the sequence specific mediators of RNAi and that even single mismatches between the siRNA duplex and the target mRNA abolish interference (abstract and page 6888).
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 Int. J. Mol. Sci. 2015, 16 5263 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).
As outlined above, it is well known that there is a high level of unpredictability in the RNAi art for therapeutic in vivo applications regarding siRNAs. 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 inhibiting cancer cell growth 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 any siRNA targeting any region of any PEPD sequence in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful inhibition of cancer growth and disruption of the association of the p53 mutant with the PEPD sequence. 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 the Examiner states that the specification is enabled "for a method of inhibiting PEPD via delivery of siRNA targeted to PEPD." Applicant agrees insofar as the application enables the use of siRNA. But the claimed method is not merely a method for "inhibiting PEPD." The claimed method refers to inhibition of association of PEPD with mutant p53, with specific p53 mutations listed in the claims.
It is noted that the format of a scope of enablement rejection is for the examiner to set forth the scope that is enabled and then to point out the scope that is not enabled. It is agreed that the instant claims are directed to more than the enabled scope.
Applicant argues that the claims are amended to specify that, by disrupting association with the PEPD the p53 mutant is freed from contact with the PEPD and the p53 mutant participates in killing of the cancer cells, which is demonstrated in the specification.
However, the specification does not demonstrate inhibition of the growth of any possible cancer having one of the instantly recited mutations via broad systemic delivery of any siRNA targeted to any region of any PEPD sequence.
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.
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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