DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendments
Applicant's amendments filed 5/27/2026 to claim 1 have been entered. Claims 3, 5, 12, 18, and 21 are canceled. Claims 1, 2, 4, 6-11, 13-17, 19, 20, and 22-25 remain pending, of which claims 1, 2, 4, and 6-11 are being considered on their merits. Claims 13-17, 19, 20, and 22-25 remain withdrawn from consideration. References not included with this Office action can be found in a prior action.
The instant amendments to claim 1 have overcome the 35 U.S.C. § 112(b), 102, and 103 rejections of record and which are withdrawn. New grounds of rejection are set forth below necessitated by in the instant amendments.
Any other rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.
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 1, 2, 4, 6-8, 10, and 11 are rejected under 35 U.S.C. 103 as being unpatentable by Mutukula (PhD dissertation, 141 pages) in view of Adil et al. (Stem Cell Reports (2018), 10, 1481-1491), Cepeda et al. (J Neurosci Res. (2019), 97, 1624-1635), and Krefft et al. (JoVE (2018), 131, e56768, 8 pages; Reference U) as evidenced by the definition of “Petri dish” (2017; The Macquarie Dictionary Publishers, Retrieved from https://access.infobase.com/article/1255094-petri-dish ; Reference V).
Mutukula teaches a method of producing a composition comprising human cortical organoids, human midbrain organoids, and human diencephalic (e.g. thalamic) organoids, the method comprising: 1) differentiating human embryonic stem cells or human induced pluripotent stem cells into forebrain organoids in suspension culture (e.g. low-attachment plate) into followed by culturing the organoids in culture media on 6 cm culture plates, and wherein the organoids express RNA transcripts indicative of neocortex, midbrain, and diencephalic/thalamic fate (subheading 2.7 and 2.8, starting with the “Feeder independent” conditions on pages 41-48; Figure 14 and 22, the 1st paragraph on page 87), reading in-part on claim 1 and reading on claim 6. Mutukula teaches neurons derived from pluripotent stem cells comprising mutations in STIL and which are associated with microencephaly (the paragraph spanning pages 39-40, and the 1st paragraph on page 90), reading on claim 2. Mutukula teaches contacting induced pluripotent stem cells in suspension culture with a dose/concentration of SB-431542 and Noggin effective to induce neural fate (pages 43-44, subheadings “Day 2” and “Day 7”, and noted as “dual SMAD-I” for dual SMAD inhibition), reading in-part on claim 4. Mutukula teaches differentiation medium comprising retinoic acid, FGF2, and EGF (p44, subheading “Day 9”), reading on claim 7. Mutukula teaches adding medium to the organoids at Day 6 lacking in growth factors (page 46-47), reading in-part on claim 10. Mutukula teaches that cerebral organoids derived from human iPSCs (see detailed methods at subheading 2.8 on pages 44-48) inherently express the thalamic marker, TCF7L2 (Figure 22 and the paragraph spanning pages 86-87), reading on claim 11.
Regarding claim 1, Mutukula does not teach human striatal spheroids/organoids. Regarding claim 1, Mutukula does not teach the embodiment of culturing the spheroids/organoids in a circle-like structure. Regarding claims 1 and 10, Mutukula is silent regarding any loop assembloids. Regarding claim 4, Mutukula does not teach an effective dose of LDN 193189. Regarding claim 4, Mutukula does not teach an effective dose of any species of SHH pathway agonist.
Adil teaches methods of deriving human striatal cell clusters (e.g. organoids) from embryonic stem cells or induced pluripotent stem cells, (Abstract; the paragraph spanning both columns on page 1488), wherein the cell clusters have a functional motor spiny neuron (MSN) phenotype (Figure 2, and page 1483, paragraph starting “To investigate functional maturation…” through the paragraph ending “…loss due to contamination.” on pages 1484), reading on the human striatal spheroids of claims 1 and 10. Adil teaches administering cell clusters comprising human striatal progenitor cells to treat subjects suffering from Huntington’s disease and develop and MSN-like phenotype in vivo (Abstract), reading in-part on claims 1 and 10. Adil teaches contacting the embryonic stem cells or induced pluripotent stem cells with effective doses of SB-431542 and LDN 193189 (designated as dual SMAD inhibition) and purmorphamine (page 1488, subheading “Striatal Differentiation”), reading on claims 4 and 8, respectively.
Cepeda teaches that microcephaly is a symptom of juvenile-onset Huntington’s disease (i.e. JHD; subheading 1.1. on page 1625), reading in-part on claim 1.
Krefft teaches methods of generating forebrain cerebral organoids from human induced pluripotent stem cells (i.e. iPSCs) (Abstract). Krefft teaches transferring neuroectrodermal aggregates to a 10 cm Petri dish prior to generation of forebrain-type organoids from said aggregates (subheadings 3 and 4 on page 3), reading on the embodiment of a Petri dish as a species of circle-like structure as evidenced by the definition of “Petri dish” (i.e. being circular) for claim 1.
Regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the invention was filed to add the human striatal cell clusters (e.g. organoids) derived from either embryonic stem cells or human induced pluripotent stem cells of Adil to the human cortical, midbrain, and diencephalic organoid composition of Mutukula. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Adil and Mutukula are directed towards methods of generating brain organoids from human embryonic stem cells or human induced pluripotent stem cells, and Adil and Mutukula are reasonably directed towards an in vitro model of microcephaly in view of Cepeda. The skilled artisan would have been motivated to do so because addition of the human striatal organoids would predictably improve upon Mutukula’s brain organoid composition as an additionally physiologically-relevant cells in vitro model of microcephaly in view of Adil and Cepeda.
Regarding the loop assembloids of claims 1 and 10, wherein clauses are generally not given (patentable) weight when they simply express the intended result of a process/method step positively recited. See M.P.E.P. § 2111.04. In this case, “wherein a loop assembloid is formed” of claim 1 is simply the intended result of coculturing the claimed hCS, hStrS, hDiS, and hMbS organoids. Therefore, the combination of the hCS, hDiS, and HMbS organoids of Mutukula with the HStrS of Adil yields a substantially identical organoid composition to the claimed organoid composition and so would inherently generate the claimed loop assembloids in the absence of any persuasive showing to the contrary. See M.P.E.P. § 2112 and particularly 2112.01(I).
Regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the circular Petri dishes of Krefft (as evidenced by the definition of “Petri dish”) for the unspecified culture dishes of Mutukula. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Mutukula and Krefft are in-part towards methods of making brain organoids from iPSCs, and because the culture dishes of Mutukula and the Petri dishes are both explicitly taught as being useful for THE SAME PURPOSE of generating brain organoids from iPSCs. Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”).
Regarding claim 4, it would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the Noggin of the LDN 193189 of Adil to the differentiation and brain organoid generation methods of Mutukula. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Adil and Mutukula are directed towards methods of generating brain organoids from human embryonic stem cells or human induced pluripotent stem cells and utilizing dual SMAD inhibitors. The skilled artisan would have been motivated to do so because the substitution of one known SMAD inhibitor, Noggin, for another known SMAD inhibitor, LDN 193189, would predictably yield a method of generating brain organoids in Mutukula’s methods by dual SMAD inhibition; see M.P.E.P. § 2143(I)(B).
Regarding claim 8, it would have been obvious to a person of ordinary skill in the art before the invention was filed to add the purmorphamine of Adil to the differentiation and brain organoid generation methods of Mutukula. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Adil and Mutukula are directed towards methods of generating brain organoids from human embryonic stem cells or human induced pluripotent stem cells. The skilled artisan would have been motivated to do so because the addition of purmorphamine would predictably yield a method of generating striatal brain organoids in Mutukula’s methods; see M.P.E.P. § 2143(I)(A).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Mutukula, Adil, Cepeda, and Krefft as applied to claim 1 above, and further in view of Rharass et al. (Journal of Biomedical Science (2017), 24:78, 16 pages).
The teachings of Mutukula, Adil, Cepeda, and Krefft are relied upon as set forth above. The human striatal cell clusters of Adil having a motor spiny neuron phenotype as cited above reads on the spinal cord spheroids of claim 9. Mutukula further teaches-ascorbic acid but not when or if it is utilized (page 36), reading in-part on claim 9. Mutukula further teaches contacting induced pluripotent stem cells in suspension culture with an effective dose/concentration of BDNF (page 44, subheading “Day 9”), reading in-part on claim 9. Adil further teaches contacting the embryonic stem cells or induced pluripotent stem cells with effective doses of BDNF, IGF1, and cAMP (page 1488, subheading “Striatal Differentiation”), reading in-part on claim 9.
Regarding claim 9, Mutukula, Adil, Cepeda, and Krefft do not teach any effective dose of L-ascorbic acid in a culture medium to generate mature spinal cord spheroids .
Rharass teaches adding an effective dose (e.g. 200 µM) of ascorbic acid to in vitro cultures of neural progenitor cells and pluripotent stem cells (e.g. embryonic stem cells) is widely used to improve neurogenesis, by enhancing reactive oxygen (ROS) metabolism with no cytotoxic induction (Abstract; Table 1), reading on claim 9.
It would have been obvious to a person of ordinary skill in the art before the invention was filed to add the effective dose of L-ascorbic acid of Rharass. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Rharass and Mutukula are directed in part towards methods of differentiating pluripotent stem cells into neural cells. The skilled artisan would have been motivated to do so because Rharass teaches adding an effective dose of ascorbic acid to in vitro cultures of neural progenitor cells and pluripotent stem cells (e.g. embryonic stem cells) is widely used to improve neurogenesis, by enhancing reactive oxygen (ROS) metabolism with no cytotoxic induction, and so the addition would therefore improve upon the brain organoid differentiation methods of Mutukula in view of Adil, Cepeda, and Krefft.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Response to Arguments
Applicant's arguments on pages 6-12 of the reply have been fully considered, but not found persuasive of error over the new grounds of rejection set forth above and necessitated by the instant claim amendments. Briefly restated, the embodiment of a circle-like structure as now required by claim 1 is fully addressed by the addition of Krefft and the definition of “Petri dish” to the rejection of the claim.
In response to applicant's argument on page 8 of the reply that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., spheroid fusion) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). If Applicant is alleging that Mutukula does not teach loop assembloid formation, wherein clauses are generally not given (patentable) weight when they simply express the intended result of a process/method step positively recited. See M.P.E.P. § 2111.04. In this case, “wherein a loop assembloid is formed” of claim 1 is simply the intended result of coculturing the claimed hCS, hStrS, hDiS, and hMbS organoids. Therefore, the combination of the hCS, hDiS, and HMbs organoids of Mutukula with the HStrS of Adil yields a substantially identical organoid composition to the claimed organoid composition and so would inherently generate the claimed loop assembloids in the absence of any persuasive showing to the contrary. See M.P.E.P. § 2112 and particularly 2112.01(I). Claim 1 only requires to the formation and coculture of the different brain organoid types such as to yield a loop assembloid, and so the claim does not recite any limitation that would otherwise compel reconsideration over Mutukula and Adil and Applicant has not yet shown by any preponderance of evidence that the combination of the hCS, hDiS, and HMbs organoids of Mutukula with the HStrS of Adil would otherwise be incapable of forming the claimed loop assembloid; see M.P.E.P. § 716.01(c). It is further noted that while Applicant is free to be their own lexicographer, “assembloid” appears to be terminology unique to Applicant and is not defined in the specification such as to structurally discriminate the claims over the methods and brain organoid compositions of Mutukula and Adil, and the examiner cannot import limitations from the specification into the claims; see M.P.E.P. § 2111.01(II) and IV).
In response to applicant’s argument on page 9 of the reply that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the arguments are not persuasive because Applicant is alleging error alone over only Mutukula and which is an inappropriate test for obviousness and none of Applicant’s arguments obviate the cited teachings above that Mutukula clearly generates organoids from iPSCs that express markers of neocortical, midbrain, and diencephalic/thalamic fate; one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Furthermore, Applicant’s arguments on pages 9-10 of the reply are not persuasive because the features upon which applicant relies (i.e., negative exclusion of the WNT and SMAD inhibition methods of Mutukula) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Independent claim 1 is generic with respect to differentiation of iPSCs to neural progenitor cells and the neural progenitor cells to the claimed spheroids.
On pages 10-11 of the reply, Applicant alleges that the claimed invention yields unexpected results and relying on post-filed teachings to “Muira”. As a starting point, Applicant has not furnished the “Muira” reference for consideration in any Information Disclosure Statement and appears to have misspelled the name of the first named author and inventor by the same name. Nevertheless, the arguments are not found persuasive because the post-filed teachings of Miura as a whole show that a narrower embodiment of the “loop assembloid” made by the claimed method is operable and operability is not a germane consideration for nonobviousness under 35 U.S.C. § 103. And, the operability of the claimed methods have not been challenged in any 35 U.S.C. § 112(a) rejection for enablement, scope of enablement, and/or written description.
See M.P.E.P. § 716.02(b), as Applicant bears the burden that the evidence relied upon should establish that any differences in results are in fact unexpected and unobvious, of both statistical and practical significance, and are reasonably commensurate to the scope of the claims. In this case, Applicant has not made any attempt to relate the post-filed teachings of Miura to the cellular structure made by the claimed method and any comparison of the properties of the cellular structure made by the claimed method to the brain organoids made by Mutukula and/or Adil (see M.P.E.P. § 716.02(a) for general examples of unexpected results). The fact that the inventor (may have) recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In this case, even of Applicant could properly establish an unexpected result it is not clear how any hypothetical unexpected result would overcome the rejections of record in-part over Mutukula, Adil, and Cepeda as there is a reasonable expectation of success to add the human striatal cell clusters (e.g. organoids) derived from either embryonic stem cells or human induced pluripotent stem cells of Adil to the human cortical, midbrain, and diencephalic organoid composition of Mutukula because both Adil and Mutukula are directed towards methods of generating brain organoids from human embryonic stem cells or human induced pluripotent stem cells, and Adil and Mutukula are reasonably directed towards an in vitro model of microcephaly in view of Cepeda. Furthermore, the skilled artisan would have been motivated to do so because addition of the human striatal organoids would predictably improve upon Mutukula’s brain organoid composition by adding additionally physiologically-relevant cells to the in vitro model of microcephaly in view of Adil and Cepeda.
Conclusion
No claims are allowed. No claims are free of the art.
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 SEAN C BARRON whose telephone number is (571)270-5111. The examiner can normally be reached 7:30am-3:30pm EDT/EST (M-F).
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/Sean C. Barron/Primary Examiner, Art Unit 1653
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