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Claims 11 and 12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected method, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/2/2025.
Claim Objections
Claim 1 is objected to because of the following informalities: the abbreviation for leukemia inhibitory factor should be “LIF” not “LIP.” Appropriate correction is required.
Claims 5-9 are objected to because of the following informalities: the word order of the preamble is not consistent with the word order provided in the claims from which they depend (“method for producing a brain organoid” versus “production method”). Appropriate correction is required.
Claim Rejections - 35 USC § 102/103
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
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) 10 and 13 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Ishii, et al (WO 2021/006107 [IDS Reference]; since this reference is in Japanese, PGPub 2022/0356443 [IDS Reference], which claims priority to this application, will be used as the official translation). Please note, the claimed brain organoid is drawn to a product-by-process claim-set. See MPEP 2113. As such, if the Examiner can provide an organoid that appears the same, regardless of the method of forming, it is the Applicant’s burden to provide evidence to suggest that the claimed organoid is different than that of the prior art.
Ishii provides for methods of making a brain organoid that parallel the claimed method. Notably, Ishii provides a SMAD inhibitor to pluripotent stem cells to form an embryoid body; embedding the embryoid body into an extracellular matrix (ECM) in the presence of a SMAD inhibitor and a GSK3β inhibitor; removing the organoid from the ECM and exposing it to LIF. See paragraph [0008]. Although Ishii does not force the organoid to express a MAPT gene, Ishii uses cells from Alzheimer subjects, wherein the organoids aggregate tau protein. See paragraph [0163]. Since these cells naturally aggregate tau protein they provide for the same function as those that are forced to express/aggregate tau protein. As such, the organoid produced by Ishii appears to be identical to that claimed. If it is not identical, the only difference would be in how the tau protein is expressed and aggregated, resulting in an obvious and predictable difference between the claimed organoid and that of Ishii; as such, if Ishii does not anticipate the claimed organoid, the claimed organoid must be an obvious variant of Ishii’s.
With respect to claim 10, Ishii provides for an organoid that appears identical to that claimed. The only difference is the manner in which the tau protein is expressed/aggregated, whether it is natural or artificially induced.
With respect to claim 13, based upon Ishii’s figures and images, it appears as though Ishii provides for the same type of tau aggregation. See Figures 7A-7C; Figures 12A-18C.
Claim Rejections - 35 USC § 103
Claims 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Ishii, et al (WO 2021/006107 [IDS Reference]; since this reference is in Japanese, PGPub 2022/0356443 [IDS Reference], which claims priority to this application, will be used as the official translation) Jaworski, et al (PLoS One, 4, e7280, 2009) and Klein, et al (European Journal of Neuroscience, 27, 1615-1625, 2008). As discussed in the 35 USC 102/103 rejections above, Ishii teaches all of the claimed steps, except for teaching a step of forcing the brain organoid to express a mutant MAPT gene and cause aggregation of tau proteins. See paragraph [0008]. Although Ishii does not teach steps of forcing the organoid to express a mutant MAPT gene, and thusly, aggregate tau proteins, Ishii does provide for an organoid that does aggregate tau proteins, because Ishii begins with cells that were acquired from subjects with Alzheimer’s disease. See paragraph [0163].
Jaworski teaches methods of inserting P301L mutant MAPT genes into mice as a means of forcing them to aggregate tau proteins. See page 1, “Abstract” section. Jaworski provides for an in vivo animal model for tau aggregation, Jaworski does not describe using this model in an in vitro brain organoid.
Similar to Jaworski, Klein teaches methods of inserting mutant MAPT genes into animals, using adeno-associated virus (AAV) vectors, as a means of creating neurodegenerative disease states. See page 1, “Abstract” section. Both Jaworski and Klein show that the ordinary artisan understands that vectors, like AAV, can be used to insert mutant MAPT genes as a means of creating a model that shows tau aggregation, like in Alzheimer’s disease. Both of these references show that these genes can be inserted using well-known and widely-used methods, in order to acquire highly predictable disease-states. Although both Jaworski and Klein teach animal models, whereas Ishii teaches an in vitro model, the ordinary artisan understands when specific models have greater utility than others; as such, there would be reasonable motivation found in the general knowledge of the ordinary artisan to provide for an organoid model, in addition to the animal models of Jaworski and Klein. See MPEP 2141.03.
While it is true that Ishii does provide for an organoid model for tau aggregation, the model of Ishii requires the cells used in the model be acquired from a subject with Alzheimer’s disease. The ordinary artisan understands that this is not ideal for several reasons. First, one must source and acquire the appropriate cells from a subject with Alzheimer’s disease; second, the artisan must ensure that these cells are screened for any other disease or pathology that may or may not be related; third, the artisan must determine if each Alzheimer’s disease subject possesses the same MAPT mutation, and if there are different mutations, they must determine how these affect tau aggregation in the model. However, if the artisan were to generate healthy pluripotent stem cells, that were later forced to aggregate tau protein by inserting a mutant MAPT gene, the ordinary artisan could wholly control what mutation is inserted and ensure that the entire population has the same mutations. This level of control is impossible if the cells are directly sourced from an Alzheimer’s disease subject. As such, even though it is not explicitly stated in the prior art, the ordinary artisan would be motivation to create the brain organoid of Ishii, with health stem cells, and later force the organoid to aggregate tau proteins, because this method would be expected to provide the ordinary artisan with a greater level of control over which mutations to investigate.
With respect to claim 1, Ishii teaches steps (a)-(c), while Jaworski and Klein provide motivation to force the organoid of Ishii to aggregate tau proteins by inserting a mutant MAPT gene.
With respect to claims 2-4, Jaworski teaches inserting P301L MAPT mutants using an AAV. See page 1, “Abstract” section; page 11, “Animals and stereotaxic injection” section.
With respect to claim 5, Ishii teaches performing the method in the presence of more than 20% oxygen. See paragraph [0097].
With respect to claim 6, Ishii teaches 3 weeks or longer. See paragraph [0089].
With respect to claim 7, since step (e) is not explicitly taught in the prior art, and is provided by the combination of Ishii with Jaworski and Klein, no reference would be expected to teach this limitation. However, the limitation is drawn to a step of forcing cells to express a mutant MAPT gene. Both Jaworski and Klein use well-known and widely used methods of infecting cells with AAV, in order to insert mutant genes into the cells; as such, it would be obvious to the ordinary artisan to ensure that the cells are entirely infected and properly expressing the mutant gene, prior to using it. Therefore, if this step takes at least 5 weeks, it would be known, and obvious to the ordinary artisan. This would be obvious, because the ordinary artisan also provides genes that tell them how many cells have been effectively infected, and the ordinary artisan would wait to carry out the next steps until all of the cells were fully infected.
With respect to claim 8, Ishii provides for a step of exposing the step cells to FGF2, wherein it is provided at less than 100 ng/mL. See paragraph [0011].
With respect to claim 9, Ishii provides feeder-free conditions. See paragraph [0012].
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 10 and 13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 7-11 of copending Application No. 17/621,535 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both inventions provide for brain organoids that have amyloid plaques caused by tau protein aggregation. As discussed in the 35 USC 102/103 rejection above (the copending application is associated with PGPub 2022/0356443, which was used in the rejections above), the copending application provides for an organoid that is formed in an identical manner to that of the instant method steps, with the one exception being that the copending application does not provide for steps of inserting a mutant MAPT gene. However, as discussed in the rejection, the claim of the instant claim-set is a product-by-process claim; since the copending application provides for the same organoid that also aggregates tau protein, they appear fundamentally and functionally identical.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID W BERKE-SCHLESSEL whose telephone number is (571)270-3643. The examiner can normally be reached M-F 8AM-5:30PM.
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/DAVID W BERKE-SCHLESSEL/ Primary Examiner, Art Unit 1651