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 .
DETAILED ACTION
RESPONSE TO AMENDMENT
Status of Application/Amendments/claims
2. Applicant’s amendment filed July 08, 2026 is acknowledged. Claims 1 and 5-6 are amended. Claims 1-7 are pending in this application. Election was made without traverse in the reply filed on December 16, 2024.
3. Claims 1-7 are under examination with respect to a lysine (K) at position 159 of SEQ ID NO: 24 or 51 substituted by an alanine (A), Serine (S) or Leucine (L) and dementia/vascular dementia/Alzheimer’s disease in this office action.
4. Applicant’s arguments filed on July 08, 2026 have been fully considered but they are not deemed to be persuasive for the reasons set forth below.
Claim Rejections/Objections Maintained
In view of the amendment filed on July 08, 2026, the following rejections are maintained.
Claim Rejections - 35 USC § 112
5. 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 1-7 stand 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 triggering GPR124/RECK-dependent brain angiogenesis and restoring blood brain barrier based on GLUT1 expression in Wnt7aa-/-mutant zebrafish by Wnt7a-aa1-278 or Wnt7a-K190A or reducing stroke volume in an animal model of stroke that is induced by transient middle cerebral artery occlusion (tMCAO) by intravenous injection to the animal model of stroke a viral vector encoding mouse Wnt7aK190A (AAV-PHP-eB-CAG-mWnt7aK190A-p2A-EGFP), does not reasonably provide enablement for a method for restoring a blood brain barrier in a subject having all forms conditions or all forms of neovascular disorders or CNS disorders recited in claims 5-7 by administering to the subject a Wnt7 polypeptide comprising SEQ ID NO:51 with an amino acid substitution recited in claim 1 as broadly claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The rejection is maintained for the reasons of record and the reasons set forth below.
Claims 1-7 as amended are drawn to a method of restoring a blood brain barrier integrity in a subject with a CNS disorder comprising neovascular dysfunction and BBB disruption, comprising administering to the subject a nucleic acid encoding a Wnt7a polypeptide or a fragment thereof capable of activating GPR124/RECK/Frizzled/LRP-mediated Wnt signaling, wherein the Wnt7 polypeptide or fragment thereof comprises SEQ ID NO:51 with a lysine (K) residue at a position corresponding to position 159 in SEQ ID NO:51 substituted by an alanine (A), serine (S) or leucine (L) residue.
The claims encompass restoring a BBB integrity in all forms of CNS disorders comprising neovascular dysfunction and BBB disruption and caused by all possible mechanisms by the claimed nucleic acid encoding the claimed Wnt7 polypeptide or fragment thereof comprising SEQ ID NO: 51 with K159A, K159S or K159L in view of paragraphs [0365]-[0367] of the published application.
Briefly, the specification provides insufficient guidance to enable a skilled artisan to practice the claimed invention without undue experimentation because the specification provides no well-established structural and functional relationship or correlation between reducing stroke volume in a mouse model of stroke by intravenous injection of an AAV encoding the Wnt7a-K190A and restoring the BBB integrity in all forms of CNS disorders comprising neovascular dysfunction and BBB disruption and caused by all possible mechanisms including dementia/vascular dementia/AD by the nucleic acid encoding the claimed Wnt7 polypeptide comprising SEQ ID NO:51 with K159A, K159S or K159L or structurally and functionally undefined fragment thereof. The specification also provides no well-established structural and functional relationship or correlation between triggering angiogenesis in the brain and the GLUT1 expression in the BBB of Wnt7aa-/-mutant zebrafish after injection of mRNA to express mouse Wnt7a-aa1-278 or Wnt7a-K190A in the Wnt7aa-/-mutant zebrafish and restoring the BBB integrity in all forms of CNS disorders comprising neovascular dysfunction and BBB disruption and caused by all possible mechanisms including dementia/vascular dementia/AD by the nucleic acid encoding the claimed Wnt7 polypeptide comprising SEQ ID NO:51 with K159A, K159S or K159L or structurally and functionally undefined fragment thereof. Thus, it is unpredictable whether administration of the nucleic acid encoding the claimed Wnt7 polypeptide comprising SEQ ID NO: 51 with K159A, K159S or K159L can restore BBB integrity in a subject suffering from all forms of CNS disorders comprising neovascular dysfunction and BBB disruption and caused by all possible mechanisms including CNS neurodegenerative diseases including dementia/vascular dementia/AD, indicating undue experimentation is required by a skilled artisan to perform while practicing the claimed invention.
Response to Arguments
On p. 6-7 of the response, Applicant argues that the rejection has been overcome in view of amendment to claim 1 by reciting restoring BBB integrity in a subject with a CNS disorder comprising neovascular dysfunction and BBB disruption and including administering a Wnt7 polypeptide the comprises SEQ ID NO:51 having a lysine residue at a position corresponding to 159 substituted by alanine, serine or lysine.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2164, MPEP §§2164.01-2164.06(b) & 2164.08, the specification provides insufficient guidance to enable a skilled artisan to practice the full scope of the claimed invention without undue experimentation because:
i. There is no well-established structural and functional relationship or correlation between the nucleic acid encoding the claimed Wnt7 polypeptide comprising SEQ ID NO: 51 with K159A, K159S or K159L or structurally and functionally undefined fragment thereof in restoring BBB integrity in a subject with a CNS comprising neovascular dysfunction and BBB disruption and the nucleic acid encoding Wnt7a-aa1-278 or Wnt7a-K190A in triggering angiogenesis in the brain and the GLUT1 expression in the BBB of Wnt7aa-/-mutant zebrafish after expression of mouse Wnt7a-aa1-278 or Wnt7a-K190A in the Wnt7aa-/-mutant zebrafish or in reducing stroke volume in a mouse model of stroke.
There is no well-established structural and functional relationship or correlation between the nucleic acid encoding the claimed structurally and functionally undefined fragment derived from the claimed Wnt7 polypeptide comprising SEQ ID NO: 51 with K159A, K159S or K159L in restoring BBB integrity in a subject with a CNS comprising neovascular dysfunction and BBB disruption and the nucleic acid encoding the Wnt7a-aa1-278 or Wnt7a-K190A in triggering angiogenesis in the brain and the GLUT1 expression in the BBB of Wnt7aa-/-mutant zebrafish after expression of mouse Wnt7a-aa1-278 or Wnt7a-K190A in the Wnt7aa-/-mutant zebrafish or in reducing stroke volume in a mouse model of stroke.
The specification provides no well-established structural and functional relationship or correlation between reducing stroke volume in a mouse model of stroke by intravenous injection of an AAV encoding the Wnt7a-K190A or triggering angiogenesis in the brain and the GLUT1 expression in the BBB of Wnt7aa-/-mutant zebrafish after injection of mRNA to express mouse Wnt7a-aa1-278 or Wnt7a-K190A in the Wnt7aa-/-mutant zebrafish and restoring the BBB integrity in all forms of CNS disorders comprising neovascular dysfunction and BBB disruption and caused by all possible mechanisms including dementia/vascular dementia/AD by the nucleic acid encoding the claimed Wnt7 polypeptide comprising SEQ ID NO:51 with K159A, K159S or K159L or structurally and functionally undefined fragment thereof. Thus, it is unpredictable whether administration of the nucleic acid encoding the claimed Wnt7 polypeptide comprising SEQ ID NO: 51 with K159A, K159S or K159L can restore BBB integrity in a subject suffering from all forms of CNS disorders comprising neovascular dysfunction and BBB disruption and caused by all possible mechanisms including CNS neurodegenerative diseases including dementia/vascular dementia/AD, indicating undue experimentation is required by a skilled artisan to perform while practicing the claimed invention.
ii. There is no well-established correlation between reducing stroke volume in the mouse model of stroke by the nucleic acid encoding the Wnt7a-K190A and restoring BBB integrity in all forms of CNS disorders comprising neovascular dysfunction and BBB disruption treated by the nucleic acid encoding the claimed Wnt7 polypeptide comprising SEQ ID NO:51 with K159A, K159S or K159L or undefined fragment thereof recited in independent claim 1.
Each type of animal models of CNS neurological diseases or CNS neurodegenerative diseases or each type of animal models of AD only reflects part of pathogenesis of the disease as taught by Tayebati (see p. 106, 1st col, 2nd paragraph, Tayebati, Mech. Ageing Dev. 2006. 127: 100-8, cited previously) and Sarter (see p. 645, abstract, Sarter, Neurosci. and Biobehav. Rev. 2004. 28: 645-650, cited previously).
Neither the specification nor the prior art provides a well-established correlation between reducing stroke volume in the mouse model of stroke by the nucleic acid encoding the Wnt7a-K190A and restoring BBB integrity in all forms of CNS disorders comprising neovascular dysfunction and BBB disruption caused by all possible mechanisms including dementia/vascular dementia/AD by the nucleic acid encoding the claimed Wnt7 polypeptide comprising SEQ ID NO:51 with K159A, K159S or K159L or structurally and functionally undefined fragment thereof recited in independent claim 1.
There is also no well-established correlation between triggering angiogenesis in the brain and the GLUT1 expression in the BBB of Wnt7aa-/-mutant zebrafish and the restoring BBB integrity in all forms of CNS disorders comprising neovascular dysfunction and BBB disruption caused by all possible mechanisms including dementia/vascular dementia/AD by the nucleic acid encoding the claimed Wnt7 polypeptide comprising SEQ ID NO:51 with K159A, K159S or K159L or structurally and functionally undefined fragment thereof recited in independent claim 1.
Thus, it is unpredictable whether administration of the nucleic acid encoding the claimed Wnt7a polypeptide comprising SEQ ID NO:51 with K159A, K159S or K159L or structurally and functionally undefined fragment thereof can restore the BBB integrity in all forms CNS disorders comprising neovascular dysfunction and BBB disruption and caused by all possible mechanisms including CNS neurodegenerative diseases including dementia/vascular dementia/AD, indicating undue experimentation is required by a skilled artisan to perform while practicing the claimed invention.
Note that the scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without such guidance, it is unpredictable whether the BBB integrity of all forms of CNS disorders comprising neovascular dysfunction and BBB disruption and caused by all possible mechanisms including CNS neurodegenerative diseases including dementia/vascular dementia/AD can be restored by the nucleic acid encoding the claimed Wnt7a polypeptide comprising SEQ ID NO:51 with K159A, K159S or K159L or structurally and functionally undefined fragment thereof; and thus the experimentation left to those skilled in the art is extensive and undue. See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Int. 1986). Thus, the skilled artisan cannot readily know how to use the claimed invention as currently claimed without further undue experimentation. In re Marzocchi, 439 F.2d 220, 223-24, 169 USPQ 367, 369-70 (CCPA 1971)” See MPEP § 2164.03.
Therefore, in view of the breadth of the claims, the lack of guidance in the specification, limited working examples, the unpredictability of inventions, and the current status of the art, undue experimentation would be required by a skilled artisan to perform in order to practice the claimed invention as it pertains to a method for restoring BBB integrity in subject suffering from all forms CNS disorders comprising neovascular dysfunction and BBB disruption and caused by all possible mechanisms including CNS neurodegenerative diseases including dementia/vascular dementia/AD by administration of the nucleic acid encoding the claimed Wnt7 polypeptide comprising SEQ ID NO:51 with K159A, K159S or K159L or structurally and functionally undefined fragment thereof.
Accordingly, the rejection of claims 1-7 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, lack of scope of enablement is maintained.
Double Patenting
6. 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 1-7 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 18 and 20 of copending Application No. 19/488303 (the ‘303 Application). The rejection is maintained for the reasons made of record and the reasons set forth below.
Briefly, although the claims at issue are not identical, they are not patentably distinct from each other because the method recited in claims 18 and 20 of the ‘303 Application recite a method of using the same material (i.e. a nucleic acid encoding a Wnt7 polypeptide comprising SEQ ID NO:51 with K159A, K159S or K159L or fragment thereof) and the same active step (administering to the subject in need thereof) in the same patient population (i.e. a CNS disorder comprising neovascular dysfunction and BBB disruption or glioblastoma, which comprises neovascular dysfunction and BBB disruption), and appears to be directed to achieving the same goal, restoring the BBB integrity in the subject. Thus, claims 1-7 of the instant Application are anticipated by claims 18 and 20 of the ‘303 Application.
Response to Arguments
On p.7 of the response, Applicant argues that the rejection is provisional and if the provisional nonstatutory double patient rejection is the sole remaining rejection, withdrawal of the rejection is appropriate and cites MPEP804 in support of the arguments.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §804 and MPEP §2131, the nonstatutory double patenting is not the sole rejection. The nonstatutory double patenting is maintained of record until a terminal disclaimer is filed.
New Grounds of Rejection Necessitated by the Amendment
The following rejections are new grounds of rejections necessitated by the amendment filed on July 08, 2026.
Claim Rejections - 35 USC § 112
7. 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 1-7 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. This is a new matter rejection.
Claims 1-7 as amended are drawn to a method of restoring a blood brain barrier integrity in a subject with a CNS disorder comprising neovascular dysfunction and BBB disruption, comprising administering to the subject a nucleic acid encoding a Wnt7a polypeptide or a fragment thereof capable of activating GPR124/RECK/Frizzled/LRP-mediated Wnt signaling, wherein the Wnt7 polypeptide or fragment thereof comprises SEQ ID NO:51 with a lysine (K) residue at a position corresponding to position 159 in SEQ ID NO:51 substituted by an alanine (A), serine (S) or leucine (L) residue.
The instant claims now recite new limitations “restoring a blood brain barrier integrity….a CNS disorder comprising neovascular dysfunction and BBB disruption”, which were not clearly disclosed in the specification and claims as filed, and now change the scope of the instant disclosure as filed. Such limitations recited in the present claims, which did not appear in the specification or original claims, as filed, introduce new concepts and violate the description requirement of the first paragraph of 35 U.S.C. 112.
The specification fails to disclose the new limitations “restoring a blood brain barrier integrity….a CNS disorder comprising neovascular dysfunction and BBB disruption”. The specification only discloses “CNS disorders comprising neovascular dysfunction”(see [0003], [0015]-[0016], [0077]; [0089]; [0364]-[0365]; [0367]-[0368]; [0372]-[0373]; [0375]-[0376]; [0407]; [0475] of the published Application) and “BBB dysfunction…stimulation of Wnt/b-catenn signaling at the dysfunctional BBB……ischemic stroke and brain cancer in mouse” ([0007] of the published Application). The specification provides no guidance as to what is encompassed in the new limitations ““restoring a blood brain barrier integrity….a CNS disorder comprising neovascular dysfunction and BBB disruption”. Accordingly, in the absence of sufficient recitation of “restoring a blood brain barrier integrity….a CNS disorder comprising neovascular dysfunction and BBB disruption”, the specification does not provide adequate written description to support the new limitation ““restoring a blood brain barrier integrity….a CNS disorder comprising neovascular dysfunction and BBB disruption’ recited in claim 1. Support is not found for the new limitations as disclosed in the original specification and thus the recitations constitute new matter absent evidence for their support. Applicant is required to cancel the new matter in the reply to this office action. Alternatively, Applicant is invited to clearly point out the written support for the instant limitations.
Conclusion
8. NO CLAIM IS ALLOWED.
9. 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.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHANG-YU WANG whose telephone number is (571)272-4521. The examiner can normally be reached Monday-Thursday, 7:00am-5:00pm EST.
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, Jeffrey Stucker can be reached at 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Chang-Yu Wang
October 5, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675
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