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 .
Note
Please note that Khaleda Hasan is now the examiner of record.
Claim Status
Applicant’s amendment filed 3/31/2025 has been entered. Claims 2-3, 7-8, 11-26, and 28 are cancelled. Claim 1 is amended to replace “capable of inhibiting” to “that hybridizes to and inhibits”. Claim 29 is new. Claims 1, 4-6, 9-10, 27 and 29 are pending and currently under examination.
Claim Rejections - 35 USC § 112
Claims 4, 9, and 10 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.
MPEP 608.01(n) states "If the base claim has been canceled, a claim which is directly or indirectly dependent thereon should be rejected as incomplete."
Claim 4 depends from claim 3, which has been canceled, therefore the metes and bounds of the claim as a whole cannot be determined.
Those claims identified in the statement of rejection but not explicitly referenced in the rejection are also rejected for depending from a rejected claim but failing to remedy the indefiniteness therein.
Claim Rejections - 35 USC § 112 - maintained
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, 4-6, 9, 10, 27, and 29 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 claims contain 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. This rejection has been modified necessitated by amendment of claim 1 replacing “capable of inhibiting” with “that hybridizes to and inhibits” and newly added claim 29 (“where SASP factors include one or more of: mmp1, mmp3, mmp13, IL-6, IL-8, and CXC-L”.
Claim 1 is drawn to the genus of polynucleotides and oligonucleotides comprising a sequence that hybridizes and inhibits expression of MDM2 mRNA, and that can function to selectively eliminate senescent cells in tissues of a brain. Claim 4 limits the scope of the polynucleotide or oligonucleotide to “an antisense oligonucleotide, siRNA or shRNA”. Amended claims require that the nucleic acid not only inhibits an MDM2 mRNA, but also must hybridize to an MDM2 RNA. However, this genus reads on miRNAs, antagomirs, aptamers, and further nucleotide sequences encoding target polypeptides, e.g., ribozymes and peptide nucleic acids. Accordingly, the specification as filed does not satisfy the written description requirement for the genus as claimed.
Applicant is referred to MPEP 2163(II)(A)(3)(a) which indicates that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure indicates that the patentee has invented species sufficient to constitute the genus. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. An applicant may show possession of an invention by disclosure of drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole. An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.
The specification discloses only two MDM2 inhibitors by reduction to practice, Nutlin-3a and RG-7112 (Examples 1-5, 21, 22, 25 and 26). These are small molecules (not polynucleotides or oligonucleotides) of related structure that function by inhibiting the interaction of MDM2 with p53 (instant specification at [0109]-[0111]). Figs. 62B and 62C show the effects of RG-7112 on senescent and non-senescent lung fibroblast cells (IMRO90 cell line) after 3 and 6 days of exposure to the agent, respectively. It is apparent from these results that RG-7112 does not selectively eliminate senescent cells as required by the claims. Instead, both senescent and non-senescent cells were eliminated by treatment with various concentrations of RG-7112. This is objective evidence of unpredictability in the art of selectively eliminating senescent cells.
The specification as filed does not disclose a single example of any polynucleotide or oligonucleotide that hybridizes to and inhibits MDM2 mRNA by actual reduction to practice or reduction to drawings, and provides no example of the elimination of any senescent cells in any brain tissue. The specification describes MDM2 inhibitors at page 29 [0105-0106] by their function. Various polynucleotide molecules that are encompassed by the claims are described on pages 42-45 [0154-0169]. However, all these sections of the specification provide merely a general description and properties of the agents encompassed by the claims. The specification provides no example of any nucleic acid encoding any antibody that can eliminate senescent cells by inhibition of MDM2, nor any nucleic acid that hybridizes to and inhibits expression of MDM2 mRNA.
Although many algorithms existed for designing inhibitory nucleic acids at the time of the invention, these algorithms generally served as guidelines for design and did not function to place one in possession of a genus of active inhibitors for a given target. For example, Angart et al. (Pharmaceuticals 2013, 6, 440-468; cited in PTO-892 mailed 7/15/2024) taught that although siRNAs were routinely used in research studies of eukaryotic biological processes, transitioning the technology to the clinic had proven challenging. Early efforts to design an siRNA therapeutic demonstrated the difficulties in generating a highly-active siRNA with good specificity and a delivery vehicle that can protect the siRNA as it is transported to a specific tissue (see abstract). One issue that renders the activity of oligonucleotide inhibitors of gene expression unpredictable is the structure of the target mRNA. Although there existed algorithms for predicting mRNA structure based on sequence alone, the actual mRNA structure in a living cell is dynamic and sequence-based predictive approaches will provide only incomplete information that can guide choices of potential target regions that are not occluded by secondary or tertiary structures (Angart at section 3.4 on page 445). See also Kwok et al. (Nature Communications 4:2971, 12 pages, 12/2013; cited in PTO-892 mailed 7/15/2024) who taught that the structures of all but the few most abundant RNAs were unknown in vivo at the time of the invention (abstract), and that empirical physical interrogation of mRNAs can dramatically improve secondary structure prediction (first paragraph on page 2). Thus because in vivo mRNA structure was unpredictable at the time of the invention, it was unpredictable as to which oligonucleotide agents would have access to target regions and provide adequate inhibition of gene expression.
With regard to shRNAs (as recited in claim 4), an additional factor rendering Fellman et al. (Molecular Cell 41, 733–746, March 18, 2011; cited in PTO-892 mailed 7/15/2024) taught that the requirements for efficient shRNA biogenesis and target suppression were largely unknown at the time of the invention, such that many predicted shRNAs failed to efficiently suppress their target (abstract). To address this issue, Fellman developed a large scale screening assay to empirically identify potent shRNAs (abstract), thus demonstrating a need to empirically identify active shRNAs despite the availability of prediction algorithms. So, while those of skill in the art are generally capable of developing nucleic acid agents that can hybridize and inhibit target gene expression (e.g. antisense oligonucleotides, siRNAs, and shRNAs, as recited in claim 4; miRNAs, antagomirs, and aptamers; and a nucleotide sequence encoding a target polypeptide, e.g., a ribozyme and a peptide nucleic acid) through the use of design algorithms, the unpredictability in the art generally requires empirical testing of agents predicted to be active by such algorithms. Accordingly the existence of predictive algorithms, and the general state of the art at the time of the invention, did not generally place one of skill in possession of specific inhibitory oligonucleotides for a given target gene, and definitely did not place one in possession of the genus of agents with the instantly claimed function of “selectively eliminating senescent cells in tissues of a brain”, particularly in view of the unpredictability evidenced by the specification. Because the specification as filed does not disclose a single example of any species of the claimed genus of senolytic agents by reduction to practice or drawings, and because the general functional description of such agents does not constitute a disclosure of relevant, identifying characteristics due to the unpredictability in the art, the specification as filed fails to disclose a representative number of species of the claimed genus, and there is a failure to meet the written description requirement.
Response to Arguments
Applicant's arguments filed 03/31/2025, with regard to the rejection of claims 1, 4-6, 9, 10, 27, and 28 for failure to meet the written description requirement, have been fully considered but they are not persuasive. Applicant asserts that the claims as amended are fully supported and satisfy the written description requirement. The claims have been amended to require a polynucleotide or an oligonucleotide comprising a sequence that hybridizes to and inhibits expression of an mRNA encoding MDM2. It is noted that this amendment addresses the issues raised in the previous rejection with regard to direct and indirect inhibition of MDM2 such that the claims now limit the polynucleotides and oligonucleotides having a sequence that hybridizes directly to and inhibits the mRNA encoding MDM2.
Applicant asserts that the application discloses and reduces to practice numerous senolytic agents, however none of these is a species of the claimed genus. The specification as filed does not disclose a single species of the claimed genus of MDM2 inhibitors. Moreover, with regard to the disclosed MDM2 senolytic agents, the available data indicate that it is unclear that RG7112 is a member of the claimed genus because it does not selectively kill senescent cells (it kills non-senescent cells as well).
Applicant asserts that the claimed function of selectively eliminating senescent cells in tissues of a brain is supported in view of demonstrations of functionality of several inhibitors in tissues other than brain, and in view of “the systemic effect as shown with transgenic mice.” However, as noted above none of these inhibitors is a species of the claimed genus of polynucleotides or oligonucleotides that hybridize and inhibit expression of mRNA encoding MDM2, particularly to the extent that such inhibition provides an effect of removing senescent cells from the tissue.
Applicant refers to Figures 62B-62C to provide evidence that MDM2 inhibition predictably provides a selective senolytic effect. This is unpersuasive because by 3 days the lowest Rg7112 concentration removed 25% of the nonsenescent cells (more than the proportion of nonsenescent cells that was removed). Nevertheless, it is unclear how these data derived from use of a small molecule affect the issue of the failure to disclose a single species of the claimed genus of inhibitors (which are not small molecules).
With regard to claim 4, Applicant argues that Fellman indicates a state of the art that placed those of skill in possession of tools to design or develop shRNAs for nearly three years prior to the filing of this application. This is unpersuasive because Fellman taught that many predicted shRNAs failed to efficiently suppress their target. Hence Fellman developed a large scale screening assay to empirically identify potent shRNAs (abstract), thus demonstrating a need to empirically identify active shRNAs despite the availability of prediction algorithms. So, while those of skill in the art are generally capable of developing nucleic acid agents that hybridize to and inhibit target gene expression (e.g. antisense oligonucleotides, siRNAs, shRNAs, and further) through the use of design algorithms, the unpredictability in the art generally requires empirical testing of agents predicted to be active by such algorithms. Applicant has not performed such testing and so was not in possession of shRNAs with the claimed activity of hybridizing and inhibiting MDM2 mRNA expression, particularly to the extent that it might remove senescent cells from brain tissue.
Therefore the rejection is maintained.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KHALEDA B HASAN whose telephone number is (571)272-0239. The examiner can normally be reached IFP, Monday - Friday 7:30am-5pm.
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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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/KHALEDA B HASAN/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636