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 .
Applicant’s amendment and response filed on 12/1/2025 has been received and entered into the case.
Claim 5 has been canceled, claim 19 is newly added, and claims 1-4 and 6-19 have been considered on the merits. All arguments have been considered.
The claim rejections under 35 USC 112(a) have been withdrawn due to the instant amendment.
The claim rejection under 35 USC 102 has been withdrawn due to the instant amendment.
The claim rejection under 35 USC 103 has been withdrawn due to the instant amendment. A new ground of rejection under 103 is presented below to address the instant amendment and a new claim.
The double patenting rejections have been modified to address the instant amendment and a new claim.
Claim Rejections - 35 USC § 103 (New Rejection)
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) 1-4 and 6-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Weeber (supra).
Weeber teaches a method of treating neurological disorders including FXS by administering a therapeutically effective amount of a repeat fragment of Reelin or a construct formed from fragment repeats of Reelin to a patient (Abstract; p.10, line 20 thru p.11, line 11). Weeber also teaches a recombinant Reelin fragment or Reelin splice fragment including those comprising R3, one without R4 and R5, i.e. R3+R6 (p.12, lines 8-15).
Weeber teaches that the construct of recombinant Reelin is inserted into a viral vector including AAV (p. 11, lines 37-39).
Regarding the Reelin fusion protein comprising an N-terminal Reelin R3 repeat encoded by SEQ ID NO:2, the SEQ ID NO:2 of Weeber (p.37) is 100% identical to the SEQ ID NO:2 of claim 1 (see the alignment presented in the previous OA mailed on 9/5/2025).
Regarding claim 1 directed to the recombinant Reelin fusion protein comprising an IgKappa signal sequence fused in frame to the N-terminal Reelin R3 repeat, Weeber teaches the presence of a signal sequence in the sequence of R3+R6 fragment (see p.14, lines 35-37; Fig. 8), and the signal peptide appears to be a native signal peptide of Reelin protein. However, Weeber does not teach the IgKappa signal peptide.
The IgGk (IgKappa) signal peptide is extremely well known in the art for the purpose of directing a protein into a secretory pathway (see Liu et al. 2016). As the Reelin fragment of Weeber is intended for secretion, and Weeber teaches the use of native signal sequence for the purpose of directing the protein into the secretory pathway, it would have been obvious to a person skilled in the art to use an alternative signal peptide/signal sequence that equivalently directs a protein into a secretory pathway to the native signal peptide. The substitution of an art-recognize equivalent is obvious (MPEP2144.06(II)).
Regarding claim 3 directed to SEQ ID NO: 5, Weeber discloses SEQ ID NO:5 (p.38) and this is 100% identical to the SEQ ID NO: 5 of claim 3 (see alignment presented in the OA mailed on 9/5/2025).
Regarding claim 4 directed to the recombinant Reelin fusion protein having SEQ ID NO: 10, Weeber teaches SEQ ID NO: 10 (p.40) that is 100% identical to the SEQ ID NO:10 of claim 4 (see the alignment presented in the OA mailed on 9/5/2025).
Regarding claim 6, Weeber teaches intracerebral injection of the Reelin vector (p.64, claim 5).
Regarding claim 7, Weeber teaches that the Reelin is bilaterally injected into the patient (p.64, claim 6). This teaching is understood that the Reelin vector is administered by a bilateral intracerebral injection.
Regarding claim 8 directed to ICV injection, Weeber teaches intraventricular injection as well as intracerebral injection. Weeber also teaches the procedure of bilateral injection into a mouse (p.50, lines 14-24). This teaching is considered to meet the ICV injection because the procedure involves drilling holes through the skull and the Hamilton needle is through the brain into the ventricles, i.e. intracerebroventricular injection.
Regarding claims 9-16, the limitations of these claims are considered as results of the claimed method. Therefore, the wherein clause of these claims does not require any additional active step other than administering the AAV vector encoding a secreted recombinant REELIN fusion protein, and they do not provide any patentable weight in determining patentability of the claimed method. Furthermore, as the method steps taught by Weeber are identical to the method steps of the instant claims, the results are expected the same.
Regarding claim 17 directed to the fusion protein comprising R6 repeat encoded by SEQ ID NO:5, as discussed above, Weeber teaches a Reelin fragment comprising R6 and the SEQ ID NO: 5 of Weeber is identical to the claimed SEQ ID NO:5.
Regarding claim 18 directed to the secreted recombinant Reelin fusion protein not comprising Reelin repeats R4 or R5, as discussed above, Weeber teaches a recombinant human Reelin protein comprising R3 fragment conjugated to the R6 fragment (R3+R6) (p.40; SEQ ID NO:10), and this recombinant protein meets the limitation of claim 18.
Regarding claim 19, Weeber teaches that vectors include AAV9, AAV5, AAV1 or AAV4 (p.11, lines 37-39).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4 and 6-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 9,962,426 in view of Weeber (supra) and Liu et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘426 patent disclose a method of improving cognitive function in a subject by administering a therapeutically effective amount of a Reelin fragment to the subject suffering from fragile X syndrome. While the ‘426 patent does not particularly disclose what the Reelin fragments are except their MW, i.e. a 180 kDa, a 370 kDa or a 450 kDa Reelin fragment, the claims of the ’426 patent do not disclose the Reelin fusion protein of the instant claims. However, Weeber teaches the Reelin fragments identical to the SEQ ID NOs: 2, 5 and 10 (as shown above), and Weeber teaches the use of these Reelin fusion fragments for treating FXS, it would have been obvious to a person skilled in the art to use the Reelin fragments of Weeber in the method of the claims of the ‘426 patent.
While the claims of the ‘426 patent do not teach the delivery of an AAV vector encoding the Reelin protein, rather the claims are directed to the delivery of a Reelin protein fragment, however, it would have been obvious to a person skilled in the art to deliver a viral vector such as AAV encoding the Reelin protein fragment or fusion protein as Weeber teaches such method for treating FXS.
Regarding the routes of delivery, Weeber teaches intracerebral or intraventricular delivery, and the ICV delivery is an obvious alternative to these routes for delivering an AAV vector encoding the Reelin fusion protein of the instant claims.
Regarding the use of IgKappa signal sequence (claim 1), while the claims of the ‘426 patent in view of Weeber do not teach the IgKappa signal sequence, however, it would have been obvious to a person skilled in the art to use IgKappy signal sequence for the secretion of the Reelin fusion protein as it is well known option in the art for directing a protein to a secretory pathway according to Liu et al.
Regarding the AAV being AAV1, AAV4, AAV5 or AAV9, Weeber teaches that the AAV vectors include the claimed serotypes.
Thus, the claims of the ‘426 patent in view of the cited references render the claimed invention obvious.
Claims 1-4 and 6-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 10,729,744 in view of Weeber (supra) and Liu et al. (supra). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘744 patent disclose a method of improving cognitive function in a subject by administering a therapeutically effective amount of a Reelin fragment to the subject suffering from fragile X syndrome. While the ‘744 patent does not particularly disclose what the Reelin fragments are except their MW, i.e. a 180 kDa, a 370 kDa or a 450 kDa Reelin fragment, the claims of the ’744 patent do not disclose the Reelin fusion protein of the instant claims. However, Weeber teaches the Reelin fragments identical to the SEQ ID NOs: 2, 5 and 10 (as shown above), and Weeber teaches the use of these Reelin fusion fragments for treating FXS, it would have been obvious to a person skilled in the art to use the Reelin fragments of Weeber in the method of the claims of the ‘744 patent.
While the claims of the ‘744 patent do not teach the delivery of an AAV vector encoding the Reelin protein, rather the claims are directed to the delivery of a Reelin protein fragment, however, it would have been obvious to a person skilled in the art to deliver a viral vector such as AAV encoding the Reelin protein fragment or fusion protein as Weeber teaches such method for treating FXS.
Regarding the routes of delivery, Weeber teaches intracerebral or intraventricular delivery, and the ICV delivery is an obvious alternative to these routes for delivering an AAV vector encoding the Reelin fusion protein of the instant claims.
Regarding the use of IgKappa signal sequence, while the claims of the ‘744 patent in view of Weeber do not teach the IgKappa signal sequence, however, it would have been obvious to a person skilled in the art to use IgKappy signal sequence for the secretion of the Reelin fusion protein as it is well known option in the art for directing a protein to a secretory pathway according to Liu et al.
Regarding the AAV being AAV1, AAV4, AAV5 or AAV9, Weeber teaches that the AAV vectors include the claimed serotypes.
Thus, the claims of the ‘744 patent in view of the cited references render the claimed invention obvious.
Response to Arguments
Applicant’s arguments with respect to the claim rejection under 35 U.S.C. 112(a) have been fully considered in view of the instant amendment to the specification, and are persuasive. The claim rejections under 35 U.S.C. 112(a) have been withdrawn.
Applicant's arguments with respect to the 103 rejection have been fully considered but they are not persuasive. As indicated above, the 102 rejection has been withdrawn due to the instant amendment to incorporate the limitation of claim 5 into claim 1. In order to address the instant amendment, a new 103 rejection is presented above.
In the response, applicant alleged that it was not reasonable for one of skill in the art to expect that a substantially truncated REELIN fragment (e.g. R36) could not only be efficiently packaged into an AAV vector, but also recapitulate the function of REELIN following successful secretion from a cell. The Examiner respectfully disagrees with the applicant’s allegation. As clearly taught by Weeber, the claimed R3+R6 REELIN fragment was specifically disclosed (see Example 1-2) and thus, one skilled in the art would know that the DNA encoding R3+R6 fragment is inserted into an AAV-9 or AAV-5 viral vector and successfully produce the REELIN fragment (Example 2 of Weeber) and the function of the fragment was determined (Example 3).
Applicant argued that it is surprising and unexpected that expression from the R36-AAV vector was confirmed in HEK-293 cells as indicated by positive anti-myc tag detection in the cell lysate and media of transfected cells. It is not clear how this expression of the R36 in the cells is considered surprising as Weeber teaches that the R3+R6 REELIN fragment was successfully expressed using AAV vectors using HEK293 cells (p.37). Also Fig. 11 of Weeber shows that R3-6 (R3456) and R3+R6 (R36) along with other fragments functional based on a receptor activation luciferase assay (Example 3). As Weeber clearly discloses that the neuronal disorder being treated includes Fragile X Syndrome, and the construct for R3+R6 REELIN fragment is shown to be expressed and functional, the result of treating at least one symptom of a human subject having FXS would be expected the same as the claimed invention.
Regarding the double patenting rejections, the rejections have been modified to address the instant amendment. Applicant’s request to hold the rejection in abeyance is not a proper response. The double-patenting rejections will not be held in abeyance. See 37 C.F.R. 1.111(b), which allows that some objections or “requirements as to form” may be held in abeyance but includes no provision for holding rejections in abeyance. Section 1.111(b) also requires applicants to respond to each rejection with “arguments pointing out the specific distinctions believed to render the claims, including any newly presented claims, patentable over any applied references.” For each rejection, for example, applicants might provide a proper terminal disclaimer (or at least indicate a willingness to submit one when double patenting is the only remaining issue); explain why the rejection is overcome by amendments; provide convincing arguments that the rejection was made in error; and/or explain why amendments or claim cancellations in the copending applications have rendered the rejection moot. If any of the conflicting pending application matures to a patent, modifying the rejection to account for claim-number changes will not constitute a new ground of rejection.
Thus, the double patenting rejections are maintained.
Conclusion
No claims are allowed.
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 TAEYOON KIM whose telephone number is (571)272-9041. The examiner can normally be reached 9-5 EST Monday-Friday.
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/TAEYOON KIM/Primary Examiner, Art Unit 1631
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