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 .
Election/Restrictions
Claims 10-16, 21, and 23-25 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 6/11/25.
Specification
The specification filed on 11/17/25 has been entered.
Response to Arguments
The response to the 37 CFR 1.105 indicates that the sequences for the aptamers in the Zhang (Award Number W81XWH-11-1-0018, pages 1-34, cited on an IDS) cannot be readily obtained. In view of this statement the reference cannot be used in a prior art rejection because it cannot be determine if the reference teaches or suggests the inhibitors set forth in the instant claims.
Applicant’s arguments, see pages 10-13, filed 11/17/25, with respect to 103 rejection based on Armour (US 20150299767) have been fully considered and are persuasive. The rejection of claims has been withdrawn because applicant’s argument that the proposed modification to convert the DNA sequence comprising SEQ ID NO:3 to a RNA sequence would render the sequence unsatisfactory for its purpose in at least two ways is found persuasive. The adapter is used to target a sequence and the sequence is the sequence being cleaved by the restriction enzyme BspQI and converting the adapter to a RNA sequence, the sequence would not be cleaved by the restriction enzyme.
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, 3, 6 and 8-9 remain and claims 36-38 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 claimed invention embraces an aptamer that binds a mediator subunit 1 (MED1)-estrogen receptor (ER) binding comprising a nucleic acid with at least 70(85)% to SEQ ID NOs: 1-10.
The specification describes making aptamers comprising SEQ ID NOs: 1-10 using SELEX an a DNA library containing 41 nucleotides random sequence flanked by constant regions, the RNA library was loaded onto an immobilized MED1 mutant (SEQ ID NO: 36) protein column and the flow-through was then incubated with purified MED1 wild type (wt), SEQ ID NO: 35. The RNA was extracted from MED1 wt protein and processed then went thru 6 rounds of SELEX. See also Figure 1A. Page 42 discuss the properties of the top 8 RNA aptamers (SEQ ID NOs: 1-8). The aptamers can bind to MED1, but not MED1 mutant proteins (Figure 6A). Aptamers B (SEQ ID NO: 1), G (SEQ ID NO: 3), P (SEQ ID NO: 4), O (SEQ ID NO: 6), K (SEQ ID NO: 7), and X (SEQ ID NO: 8) significantly disrupt the interaction between ER and MED1 (Figure 6B). Aptamers R (SEQ ID NO: 2), P (SEQ ID NO: 4), T (SEQ ID NO: 5), O (SEQ ID NO: 6), X (SEQ ID NO: 8) were able to strongly inhibit estrogen-dependent ER-reporter gene expression (Figure 6C). Aptamers P and T have the most significant effects on growth (Fig 6D). Based on the results, RNA aptamer P (SEQ ID NO: 4) was selected as the top MED1 aptamer candidate because it consistently demonstrated capabilities in binding MED WT, disrupting ER/MED1 interaction, ER-dependent transcriptional activities and significant inhibition of both growth and migration of breast cancer cells. The working examples disclose that there is a variation of function amongst species of aptamers.
The claims read on inhibitor having at least 70(85)% identity to SEQ ID NOs: 1-8 or having at least 20 or more consecutive bases to the sequence of these sequences. SEQ ID NOs: 2-5 and 7-8 are 40 nucleotides (nts) in length; SEQ ID NOs: 1 and 6 are 39 nts; SEQ ID NO: 9 is 34 nts; SEQ ID NO: 10 is 53 nts. The claimed inhibitor embraces sequences with at least 20 nts of the sequences.
A search of SEQ ID NO: 9 (34nts) indicates that SEQ ID NO: 4 and 10 contain a sequence that is 100% identical to SEQ ID NO: 9. SEQ ID NOs: 1-3 and 5-8 do not appear to share a region of nucleotides with SEQ ID NOs: 4, 9 and 10. SEQ ID NOs: 1-3 and 5-8 do not appear to share a common region of nucleotides.
The specification provides written support for SEQ ID NOs: 1-10 and SEQ ID
NOs: 4 or 10 that comprise at least SEQ ID NO: 9 that are MED1-ER binding inhibitors.
The specification does not appear to provide a core structure (nucleotide sequence) of the aptamers comprising SEQ ID NOs: 1-10 that is considered essential for the function (desired biological activity, MED1-ER binding inhibitor).
The specification does not appear to disclose what nucleotides of SEQ ID NO: 8 are considered the LXXLL-binding portion. In addition, X is any amino acid.
The written description requirement for a nucleic acid sequence having at least 70% to SEQ ID NOs: 1-10 or at least 20 or more consecutive bases of SEQ ID NOs: 1-10 is not satisfied through sufficient description of a representative number of species. The specification does not describe what nucleotide from these sequences can be removed or are considered essential for the desired biological activity.
While the as-field specification and the prior art (Lee et al. Biomedicines 11, 356, pages 1-22, 2023) disclose that aptamers can be made using well known techniques, the properties of each aptamer have to be empirically determine to see if they have the desired biological activity. “The claimed invention itself must be adequately described in the written disclosure and/or the drawings.” “For example, disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional.” See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)(“*knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties). See MPEP 2163(1)(3)(a).
The application does not provide a representative number of species, which adequately described and are considered representative of the entire genus of inhibitors. The sequence search indicates that there is a substantial variation within the genus of inhibitors. The specification of the instant disclosure does not describe a sufficient variety of species to reflect the variation within the genus. See Enzo Biochem., 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)(‘[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). See also MPEP §2163.
In view of the foregoing, it is clear that the specification of the instant disclosure fails to convey to the skilled artisan that the applicant had possession of the claimed inhibitor in claims 1, 3, 6, 8-9 and 36-38 as of the effective filing date.
Response to Arguments
Applicant's arguments filed 11/17/25 have been fully considered but they are not persuasive.
Applicant states that the level of skill and knowledge in the art is high, which weighs in favor of finding that the specification as filed is sufficient to satisfy the written description requirement (see MPEP 2163(I)(A) and 2163.04).
While it is acknowledged that one of skill in the art can make an aptamer comprising at least 75%(85%) identity to a sequence selected from the group consisting of SEQ ID NOs: 1-10. This does not provide written support for the genus of inhibitors having the desired biological activity (MED1-ER binding inhibitor). The prior art (Lee et al. supra) disclose that aptamers can be made using well- known techniques, however, the properties of each aptamer have to be empirically determine to see if they have the desired biological activity.
Applicant also indicates that the Office has acknowledged that the specification provides written support for SEQ ID NOs: 1-10 and SEQ ID NOs: 4 and 10 that comprise SEQ ID NO: 9.
In response to applicant’s arguments that the specification discloses that the claimed aptamers bind the key LXXLL motif (SEQ ID NO: 35) of MED1 to interrupt the ability of MED1 to bind estrogen receptor, which provides guidance for the structure of the aptamers (paragraph 42), the argument is not found persuasive because the specification does not appear to describe what nucleotides from SEQ ID NOs: 1-10 are considered essential for the desired biological activity. The majority of the working examples appear to be limited to MED1SP (SEQ ID NO: 9/10). In addition, paragraph 139 discloses that while the interaction of ER/MED1 is disrupted by MED1SP, it was found that other transcriptional ER co-activators like SRC and PGC-18, both of which contain LXXLL (SEQ ID NO: 35) motifs, can still bind ER (Fig. 2D). This would indicate that in addition to LXXLL motif, there are additional structures of the aptamers involved in observing the desired biological activity.
Applicant’s argues the rejection should be withdrawn by arguing that the structure of the aptamers are described in the specification by disclosing the structure of the aptamer (nucleotide sequence). See also paragraph 22. Paragraph 22 discloses the isolation of MED1 LXXLL (SEQ ID NO: 35) motif targeting RNA aptamers made using SELEX.
The argument is not found persuasive because while the specification (including paragraph 22) provides the nucleotide sequence for eight aptamers (SEQ ID NOs: 1-8), the specification does not disclose what nucleotides from the aptamers can be removed and still possess the desired biological activity (MED1-ER1 binding inhibitor).
In response to applicant’s argument that the specification further discloses that the tertiary structure of the claimed aptamers depicted in Figure 2A can be achieved with different base pairings (specification paragraph 49 and 52) and taken together with SEQ ID NOs: 1-10, the applicant submits that the requirement for a partial structure of the claimed aptamers is satisfied, the argument is not found persuasive because, as stated in the rejection of record, there is variation amongst nucleotides set forth in SEQ ID NOs: 1-10. Paragraphs 49 and 52 are limited to one RNA aptamer, RNA aptamer P (SEQ ID NO: 4) and a shortened variant thereof (SEQ ID NO: 9). Instant SEQ ID NOs: 1-3 and 5-8 do not appear to share a region of nucleotides with SEQ ID NOs: 4, 9 and 10. SEQ ID NO: 4 or 9 do not appear to be representative of the genus of aptamers embraced by the claimed invention. The specification does not appear to describe what nucleotides of SEQ ID NOs: 1-3 and 5-8 are considered essential for the desired biological activity. SEQ ID NOs: 1-3 and 5-8 have 39 or 40 nucleotides in length. The specification does not appear to describe what 6-9 nucleotides can be removed, replaced or substituted and still retain the desired biological activity. While the as-field specification and the prior art (Lee et al. supra) disclose that aptamers can be made using well- known techniques, the properties of each aptamer have to be empirically determine to see if they have the desired biological activity.
Applicant further argues that the specification further discloses a reasonable structure-function correlation because the specification discloses that the tertiary structure and binding of the aptamers to the LXXLL motif of MED1 interrupts the ability of MED1 to bind ER, thereby inhibiting binding of MED1 to ER and growth, migration and invasion of cancer cells (see also Figures 2-9 and throughout the examples of the specification as filed).
The argument is not found persuasive because the majority of examples are directed to studying MED1SP (SEQ ID NOs: 4 and shortened version set forth in SEQ ID NO: 9).
The results in Figures 1 and 6 appear to be the only working examples describing the structure (nucleotide sequence) and/or function of the aptamers S (control), R (SEQ ID NO: 2), B (SEQ ID NO: 1), G (SEQ ID NO: 3), P (SEQ ID NO: 4), T (SEQ ID NO: 5), O (SEQ ID NO: 6), K (SEQ ID NO: 7) and X (SEQ ID NO: 8).
Figure 6B appears to the an experiment for determining the interaction between ER1 and MED1. The specification states that GST pull-down assays demonstrated the ability of aptamer candidates B, G, P, O, K, and X to significantly disrupt the interaction between ER and MED1 (Fig. 6B). Upon observation of the intensity of the bands for MED1, it appears that R, T and O has similar intensity to the control S. Aptamers B, G, P, K and X appeared to have similar amounts. This indicates a variation of the desired biological activity amongst species of claimed aptamers.
In addition, paragraph 139 of the specification appears to disclose that in addition to LXXLL motif, there are additional structures of the aptamers involved in observing the desired biological activity.
Furthermore, with respect to written support based on the examples disclose in the specification, the specification does not appear to disclose what nucleotides of the instant SEQ ID NOs: are considered the LXXLL-binding portion. For example, Figures 2B-2F and paragraphs 138-139 in the working examples do not disclose that SEQ ID NOs: 1-3 and 5-8 possess the desired functional limitation.
In response to applicant’s arguments that the specification provides a method of making the claimed aptamers (see paragraphs 49-52), the argument is not found persuasive because while it is acknowledged that a skilled artisan could make the aptamers, the skilled artisan would have to further experiment with the aptamers to determine if they had the desired function (MED1)-(ER) binding inhibitor. See MPEP 2163, Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017).
Thus, the written description remains for the reasons of record.
Allowable Subject Matter
Claims 4 and 5 remain objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The prior art does not teach or suggest a RNA sequence comprising SEQ ID NO: 9 or 10. Claim 35 is in condition for allowance.
Free of the prior art:
A search of the prior art does not disclose any sequence with at least 70% identity to either RNA sequence. A RNA sequence comprising a sequence having at least 70% identify to a sequence selected from the group consisting of SEQ ID NOs: 1-10 appear to be free of the prior art. Claims 1, 3, 6, 8-9 and 36-38 are free of the prior art because the prior art does not teach or suggest making a RNA sequence comprising at least 70% identity to SEQ ID NOs: 1-10.
Conclusion
See attached PTO-326 for disposition of claims.
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 Brian Whiteman whose telephone number is (571)272-0764. The examiner can normally be reached on Monday thru Friday; 6:00 AM to 3:00PM.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636