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 .
Claim Status
Claims 1-19 are pending in the application.
Election/Restrictions
Applicant’s election with traverse of Group I, claims 1-7 and 18-19, in the reply filed 6/17/26 is acknowledged. The traversal is on the ground(s) that unity of invention under PCT Rule 13.1 exists because the groups are not independent and distinct and a lack of any serious search and examination burden. This is not found persuasive because burden is immaterial to a finding of lack of unity of invention pursuant to Patent Cooperation Treaty (PCT) Rule 13.1. See MPEP 1893.03(d). The requirement is still deemed proper and is therefore made final. Claims 8-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim.
Objections to the Disclosure
Paragraphs [0044] and [0047]-[0048] in the specification each refers to colors (e.g., red, yellow) in the drawings; however, color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection will not be held in abeyance.
Claim Objections
Claims 7 and 19 are objected to because of the following informalities: claims 7 and 19 each recites the phrase “the organoid has . . . in major axis diameter or in diameter,” wherein it is either “1 mm or more” or “1 mm to 2 mm,” respectively. For grammatical reasons, this would be clearer if rewritten as the organoid has “a diameter or major axis diameter of” “1 mm or more” or “1 mm to 2 mm,” respectively, or a similar alternative wording avoiding the construction of “in diameter.” Appropriate correction is required.
Claim Interpretation
The MPEP (2111.01(II)) notes it is generally improper to read a specific order of steps into method claims unless, as a matter of logic or grammar, there is an implicitly required order that one step must precede a second step. The broadest reasonable interpretation of claim 3 has no implied order by either logic or grammar for the culturing of the obtained EB in the second or third culture medium, which are each necessarily different from each other due to the second factors and each are different from the first culture medium due to the first factor(s).
Claim 2 recites a “second” culture medium comprising a “second factor” necessarily comprising “a Wnt inhibitor” but not containing the first factor(s) of the “first” culture medium, which may optionally comprises a “Wnt inhibitor” as recited in claim 1. Thus, claim 2 is interpreted as limiting the first factor(s) to comprising TGF-β signaling pathway inhibitor and/or a GSK inhibitor.
In claims 9, the term DARPP32 “positive” or GABA “positive” is interpreted as meaning a cell that expresses a detectable amount of DARPP32 or GABA protein, respectively, as determined by any method known in the prior art.
Claim Rejections - 35 USC § 112(a) - Written Description
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 2-7 and 18-19 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.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicant’s effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of.
Claims 2-7 and 18-19 are directed to methods for producing lateral ganglionic eminence (LGE) neurospheres and/or striatal-like organoid from an embryoid body (EB) in culture using a series of different culture media.
Claim 2
Claim 2 is broad in that the method comprises the genus of “patterning factors for sonic hedgehog pathway activation.”
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described. In the instant case, the specification only describes such patterning factors that are soluble agonists. However the prior art teaches patterning factors for sonic hedgehog pathway activation include membrane bound receptors like Patched (PTC) receptor and Smoothened (SMO) as well as intracellular GLI transcription factors (see e.g., Roberg-Larsen et al., Biochem Biophys Res Commun 446: 669-74 (2014) at abstract).
The skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of the scope methods for any such “patterning factor.” Nothing in dependent claims 3-7 and 18-19 cures this deficiency.
Claim 3
Claims 3-7 and 18-19 are directed to methods for producing a striatal-like organoid from an embryoid body (EB) in culture using a medium comprising BDNF and/or ascorbic acid but excluding a Wnt inhibitor, sonic hedgehog pathway activator, and activin as well as a TGF-β signaling pathway inhibitor, such as a GSK inhibitor.
Claim 3 is broad in that the order of the second and third culture media is ambiguous as both are performed on the “obtained EB” without the impermissible importation into the claim of subject matter from the specification (see MPEP 2111.01(II)). This could mean that the steps in claim 2 are performed in parallel to those in claim 3 or they are performed sequential in either order. However, the written description is limited to wherein the LGE neurosphere producing step is necessarily performed prior to and used for the striatal-like organoid producing step. As the prior art fails to teach the reverse order, the skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of a method to predictably produce striatal-like organoids from an EB culture lacking LGE. Adequate written description requires more than a mere statement of an intended prophetic result of practicing the invention and reference to the broadly claimed method described only at a high level of generality. Nothing in dependent claims 4-7 and 18-19 cures this deficiency.
Thus, the skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of a method to predictably produce striatal-like organoids or even the apparent requisite intermediate LGE neurospheres, over the scope the claims regarding the genus of any patterning facto for sonic hedgehog signaling or the ambiguity of applying the third culturing step to any EB. Adequate written description requires more than a mere statement of an intended result of practicing the invention and reference to the broadly claimed method or genus of factors described only at a high level of generality.
35 USC § 112(a), Scope of Enablement
Claims 3-7 and 18-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, while being enabled for inducing striatal differentiation of LGE neurospheres, the specification does not enable any person, skilled in the art to which it pertains or with which it is most nearly connected to, to direct striatal differentiation of EB merely by culturing an EB obtained from claim 1 with the third culture medium.
The claims are directed to methods of using cell culture conditions to intentionally induce neural differentiation of either stem cells or LGE neurospheres to obtain a striatal-like organoid. While the prior art teaches how to direct striatal neural differentiation of LGE progenitor cells (organoids comprising LGE resembling cells) in culture (Miura et al., Nat Biotechnol 38: 1421-130 (2020), IDS ref.; at pg. 1421, right col., 1st para., Fig. 1c, Extended Data Fig. 3), the prior art is silent as to a method according to only the third medium in the absence of first forming any LGE progenitor.
Thus, these aspects of using must be shown to a reasonable extent so that one of the ordinary skills in the art would be able to practice the invention without any undue or unreasonable burden on such artisan. However there are no working examples provided, and instead the instant application is silent to accomplishing this method as claimed. The dependent claims fail to add any enabling active step to accomplish the aforementioned.
As there is no evidence in the instant application or the prior art that the scope of the claims could predictably result in one of the recited results and undue experimentation would be required to fill these gaps in the application and prior art. In summary, the claims are rejected under 35 U.S.C. 112(a) because the specification does not reasonably provide enablement to a person skilled in the art to which it pertains or with which it is most nearly connected to perform the method over the full claim scope of any of claims 3-7 and 18-19, wherein the EB lacks LGE progenitor cells. Given the lack of working examples, the limited guidance provided in the specification, and the lack of guidance in the prior art, undue and/or unreasonable experimentation would have been required for one skilled in the art to produce the recited result in claim 3. However applicant is invited to furnish evidence to the contrary.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(B) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5-6 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 5 recites “D1 and/or D2 MSN,” which ambiguous and unclear as to whether this term has or does not have any antecedent basis, and thus may refer either to a specific MSN marker of claim 4 or a new feature of the organoid. Claim 6 is included in this rejection for depending from indefinite claim 5.
Claim 6 recites the phrase expresses “all of interneuron markers,” but all interneuron markers are not defined by the claims or the instant application. Instead, the specification provides non-limiting representative species and non-exhaustive examples ([0021], [0026], [0061]).
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kwak (Kwak et al., Stem Cells 38 (6): 727-40 (2020)).
Regarding claim 1, Kwak discloses a method of culturing an embryoid body (EB) in a culture medium (BGM) comprising a TGF-β signaling pathway inhibitor (e.g., BMP inhibitors Noggin, SB431542, dorsomorphin, A83-01, and/or LDN 193189) and/or a Wnt inhibitor (CHIR99021 or IWP-2) (pg. 728, right col., last para., to pg. 729, left col., 3rd para.; Fig. 1A-B; Supplementary Methods, 2nd para.).
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Amimoto (Amimoto et al., Stem Cell Res 55: 102486 (2020)).
Regarding claim 1, Amimoto discloses a method of culturing an embryoid body (EB) in a culture medium comprising a TGF-β signaling pathway inhibitor (e.g., LDN 193189 and A83-01) and/or a Wnt inhibitor (XAV939) (pg. 4, left col., 1st para. and last para.; Fig. 1A).
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 1-7 and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Pasca (WO2021087145, IDS ref.) in view of Amimoto (Amimoto et al., Stem Cell Res 55: 102486 (2020)).
Regarding claim 1, Pasca teaches methods comprising culturing in a culture medium containing a TGF-β signaling pathway inhibitor and a Wnt inhibitor to obtain organoids comprising striatal cells (i.e., striatal spheroids) ([0058], [0134]; claims 7-8, 11, and 23-24 and 26; Example 2; FIG. 1A). Pasca does not expressly teach using an embryoid body intermediate to produce generic neurospheres or eventually striatal neurospheres; however Pasca teaches human pluripotent stem cells (hiPS) aggregated into spheroids using microwells (Fig. 1A, Example 2), which according to Amimoto can be made via embryoid-like body aggregates (pg. 4, left col., 1st para.). Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to modify the method taught by Pasca to first comprise a method step of creating embryoid bodies from iPS and culture the embryoid bodies in the medium comprising a TGF-β signaling pathway inhibitor and a Wnt inhibitor to induce neuronal differentiation. One of ordinary skill in the art would be motivated to use either method already known in the art, chosen from a embryoid body or neurosphere-only intermediate.
Regarding claim 2, Pasca teaches inducing specific neural fates by culturing in a medium comprising both a Wnt inhibitor (e.g., IWP-2) and activin A or a sonic hedgehog pathway pattern factor (agonist), e.g., to obtain LGE progenitors and striatal or midbrain spheroids ([0054]-[0059], [0066]-[0067], Example 2, FIG. 1). Further, Amimoto teaches a similar method wherein a later culturing medium lacks the TGF-β inhibitors LDN 193189 and A83-01 and lacks the Wnt inhibitor XAV939 while containing the sonic hedgehog pathway activator (agonist) purmorphamine to make striatal neurospheres (Fig. 1, Condition 2; Abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to modify the method taught by Pasca to comprise a subsequent method step of differentiating cells of the embryoid bodies by culturing in a medium comprising a sonic hedgehog pathway agonist, the Wnt inhibitor IWP-2 and activin A but not the TGF-β signaling pathway inhibitor LDN 193189 and/or A83-01 nor the Wnt inhibitor XAV939. One of ordinary skill in the art with the goal of obtaining striatal/midbrain organoids would be motivated to used media components already validated in the prior art for prior art purposes.
Regarding claim 3, Pasca teaches generating striatal-like neurons from neural progenitor cells in the spheroids (e.g., a midbrain-striatal aggregate resembling LGE) by culturing in a medium comprising BDNF and/or ascorbic acid ([0122], [0133], [0060], [0072], Example 2).
Regarding claims 4-7 and 18-19, although not all of these features are expressly taught, the combination of Pasca and Amimoto teaches the same method steps as detailed above, thus, the recited effects are expected to be produced inherently by performing the method as taught by the prior art absent evidence to the contrary and in view of the logic of the claims as presented lacking any additional active step. Further regarding claims 4, 6 and 18, Pasca teaches wherein such medium culturing produces cells differentiated into DARPP32 and/or NeuN expressing mature medium spiny neurons (FIG. 1D-E) and GFAP expressing glia (FIG. 2H-I).
Thus, the claimed invention as a whole is prima facie obvious before the effective filing date in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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