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 response to the previous Office action, dated July 23, 2026, has been received. By way of this submission, Applicant has amended the specification and claims 1, 2, and 9, cancelled claims 3, 4, 6, and 13, and introduced new claims 14-23.
Claims 1-2, 5, 7-12, and 14-23 are pending in the application. Claims 5, 7-8, and 10-12 remain withdrawn from consideration, pursuant to the Restriction Requirement mailed February 26, 2026.
Claims 1-2, 9, and 14-23 are therefore under examination before the Office.
The rejections of record can be found in the previous Office action, dated May 21, 2026.
Specification
The specification was previously objected to due to the presence of embedded hyperlinks.
Applicant's amendment to the specification has addressed this issue, and this objection is hereby withdrawn.
Claim Objections
Claim 6 was previously objected to due to minor informalities.
Applicant's cancellation of claim 6 has rendered this objection moot, and it is withdrawn.
Response to Arguments
Applicant argues that neither Chen nor Park teaches every aspect of the claims as amended; specifically, Chen and Park do not teach the use of a CRISPR/Cas9 system to edit the BMPR1A gene, nor ex vivo gene editing of neural stem cells and expansion for administration to a patient.
Applicant's arguments in view of the amendments of the claims have addressed this issue, and the prior rejection under 35 U.S.C 103 over Chen in view of Park is hereby withdrawn.
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, 9, and 14-20 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is a new grounds of rejection, necessitated by Applicant’s amendments to the claims.
The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement 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) (reversing the PTO’s determination that claims directed to methods for detection of hepatitis B surface antigens did not satisfy the enablement requirement). In Wands, the court noted that there was no disagreement as to the facts, but merely a disagreement as to the interpretation of the data and the conclusion to be made from the facts. In re Wands, 858 F.2d at 736-40, 8 USPQ2d at 1403-07. The court held that the specification was enabling with respect to the claims at issue and found that "there was considerable direction and guidance" in the specification; there was "a high level of skill in the art at the time the application was filed;" and "all of the methods needed to practice the invention were well known." 858 F.2d at 740, 8 USPQ2d at 1406. After considering all the factors related to the enablement issue, the court concluded that "it would not require undue experimentation to obtain antibodies needed to practice the claimed invention." Id., 8 USPQ2d at 1407.
Breadth of claims and nature of invention
The claims are drawn to a method of treating a subject having Alzheimer's Disease, comprising administering to the subject a therapeutically effective amount of a CRISPR/Cas system comprising a guide RNA that targets a polynucleotide encoding BMPR1A. This is interpreted to mean administering a CRISPR/Cas-based system and a guide RNA directly to a living patient with Alzheimer's Disease.
State of the art and the level of ordinary skill
At the time of the effective filing date, the level of ordinary skill to treat Alzheimer's Disease was high, requiring advanced knowledge of medicine and cell biology, typically requiring a doctoral degree and several years' experience. As of the effective filing date of December 11, 2020, no FDA approved treatments using CRISPR-Cas9 technology existed. The first such approved therapy, exagamglogene autotemcel (CasgevyTM) for the treatment of sickle cell disease, was not approved until December 2023 (Ann Med Surg (Lond). 2024 May 15;86(8):4555–4559). This treatment relies upon ex vivo manipulation of cells by CRISPR/Cas technology and subsequent reinfusion. No in vivo uses of CRISPR/Cas technology have been approved for use by the FDA.
The level of predictability of the art
Pharmaceutical therapies in the absence of in vivo clinical data are unpredictable for the following reasons; (1) the protein may be inactivated before producing an effect, i.e. such as proteolytic degradation, immunological inactivation or due to an inherently short half-life of the protein; (2) the protein may not reach the target area because, i.e. the protein may not be able to cross the mucosa or the protein may be adsorbed by fluids, cells and tissues where the protein has no effect; and (3) other functional properties, known or unknown, may make the protein unsuitable for in vivo therapeutic use, i.e. such as adverse side effects prohibitive to the use of such treatment. See page 1338, footnote 7 of Ex parte Aggarwal, 23 USPQ2d 1334 (PTO Bd. Pat App. & Inter. 1992).
The amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention based on the content of the disclosure
The specification does not give any guidance or example of how the ordinary artisan is able to treat Alzheimer's Disease by administering a CRISPR/Cas-based system directly to a living patient. At no point was a CRISPR/Cas-based system administered to a living patient. The specification does not teach how to extrapolate data obtained from various in vitro or in vivo observations as well as clinical experience with a CRISPR/Cas-based system to the development of effective methods of treating Alzheimer's Disease.
There is insufficient guidance and direction as well as objective evidence provided for treating Alzheimer's Disease by the claimed method. In view of the lack of predictability of the art to which the invention pertains, undue experimentation would be required to practice the claimed method with a reasonable expectation of success, absent a specific and detailed description in Applicant's specification of how to effectively use the claimed technology to treat Alzheimer's Disease, and absent working examples providing evidence which is reasonably predictive that the claimed method is effective for treating Alzheimer's Disease.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. MPEP 2164.02. In view on the quantity of experimentation necessary, the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trial and error to practice the claimed invention.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Rejections - 35 USC § 103
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.
Claims 2 and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Porteus (US20170298348A1) in view of Chen ("Inhibiting The Bmp Pathway Rescues Neural Stem Cell Defects In Alzheimer's Disease" ProQuest Dissertations, November 20, 2019, cited in IDS) in view of Park (Nat Neurosci. 2019 Apr;22(4):524-528, cited previously). This is a new grounds of rejection, necessitated by Applicant's amendments to the claims.
Porteus teaches a method of treating neurodegenerative diseases, comprising isolating human neural stem cells, genetically modifying isolated human neural stem cells, and administering said genetically modified neural stem cells to a patient (para. 0231-0232).
Porteus further teaches expanding the genetically modified isolated human neural stem cells before administering into the patient (para. 0231-0232).
Porteus further teaches that the neural stem cells may be autologous or allogeneic (para. 0218), which is pertinent to claims 21-22.
Porteus further teaches that the neurodegenerative disease to be treated may be Alzheimer's Disease (para. 0144 and 0224).
Porteus further teaches that the genetic modification may be performed with an RNA-guided CRISPR/Cas system (para. 0050).
However, Porteus does not teach targeting a polynucleotide encoding BMPR1A.
Chen teaches that BMP signaling is increased in a model of Alzheimer's Disease, and that self-renewal defects seen in Alzheimer's Disease neural stem cells can be rescued by employing a small molecule inhibitor of BMP (page 64, last paragraph). Chen also teaches that increased BMP signaling may be the cause of increased astrogliosis seen in Alzheimer's Disease (page 68, last paragraph). Chen also teaches that use of a BMP receptor inhibitor rescues self-renewal deficits in Alzheimer's Disease, suggesting that this may treat the disease (page vi, also see page X: "A BMPR Inhibitor Rescues Neural Stem Cell Deficits in Human Alzheimer's Model").
Chen further teaches that inhibition of BMP signaling by administration of LDN-193189 increases self-renewal of cells (Figure 31). According to Applicant's specification at paragraph 0061, LDN-193189 is a small molecule inhibitor of BMPR1A ("In some embodiments, the small molecule inhibitor is LDN193189 (or DM3189; CAS No. 1062368-24-4). See e.g., WO Patent Publications WO2009/114180, WO2012/100229, all of which are incorporated herein by reference for teaching of the LDN193189 small molecule inhibitor.").
Park teaches that gene editing with CRISPR/Cas9 is a useful method to inhibit activity of a protein for the purpose of treating Alzheimer's Disease (Figure 2). Park also teaches that this method is more efficient than chemical inhibition (page 527, left column).
It would have been prima facie obvious for a person of ordinary skill in the art as of the effective filing date to combine the teachings of Porteus, Chen, and Park to arrive at the claimed invention. An ordinary artisan would have been motivated to do so, and have a reasonable expectation of success, since all of Porteus, Chen, and Park are concerned with treatments for Alzheimer's Disease. Treatments for Alzheimer's Disease with neural stem cells that have been genetically modified with CRISPR/Cas technology were known in the art according to Porteus. Chen teaches that inhibition of BMPR1A by means of a small molecule increases self-renewal of cells in Alzheimer's Disease. Park teaches that the use of CRISPR/Cas technology is superior than using a chemical to inhibit a gene in the context of Alzheimer's Disease treatment. One of ordinary skill could target BMPR1A as a method to increase self-renewal of cells in Alzheimer's Disease according to the teachings of Chen, and use CRISPR/Cas technology to inhibit this gene according to the teachings of Park, for use in the method of Proteus. Each component of the combination would perform its known, usual function, and the combination would yield nothing more than predictable results.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Mishina (US20100292454A1) teaches that inhibitors of BMPR1A are useful for promoting neuronal regeneration (para. 0007). Mishina also teaches that inhibition of BMPR1A is useful for treating Alzheimer's disease (para. 0018).
No claim is 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 PETER JOHANSEN whose telephone number is (571)272-0280. The examiner can normally be reached Monday-Friday, 6:00 to 2:00.
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, Samira Jean-Louis can be reached at (571) 270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PETER JOHANSEN/Primary Examiner, Art Unit 1642
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