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 .
Claim Status
Claims 1-5, 14-15, 17, 19, 21-22, 25, 31 and 55-58 are pending.
Claim 31 is withdrawn.
Claims 1-5, 14-15, 17, 19, 21-22, 25 and 55-58 are under examination.
Maintained Objections to Specification
Browser-Executable Code
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (www.evinet.org/ pg. 72). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
New Claim Objections
Claim 57 is objected to because of the following informalities:
Claim 57 recites “SB 431542 and SB-505124” which appears to be missing a hyphen between “SB” and “431542.”
Appropriate correction is required.
New 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 1-5, 14-15, 17, 19, 21-22, 25 and 55-58 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.
In the amendment filed on 16th, December, 2025, the claims were amended to include the following limitations which appear to be new matter. The claims are new or amended claims, the support for the limitations is not apparent, and applicant has not pointed out where the limitations are supported (see MPEP 2163 (I)).
Claim 1 was amended to recite the at least one activator of Hh signalling increases smoothened signalling and/or “activates GLI transcription factors.”
This new limitation appears to be new matter. A review of the originally filed specification by the Examiner did NOT find any specific basis for the recited limitation. The disclosure (including the specification, claims and sequence listing) as originally filed, does not contain an explicit recitation of the limitation. The closest support for such a limitation of “activates GLI transcription factors” is the disclosure of specific species of activators of Hh signalling including 8 specific species of Sonic Hedgehog (SHH), Indian hedgehog (IHH), Desert hedgehog (DHH), purmorphamine, Smoothened agonists (SAGs) such as SAG 1.3 (Hh- 1.3), Hh-1 .2, Hh-1 .4, Hh-1 .5 (pg. 20). 8 specific species does not provide support for the full breadth of the genus of activators of Hh signalling that have the function of “activates GLI transcription factors.”
Claim 19 was amended to include “a CYP26 inhibitor.”
This new limitation appears to be new matter. A review of the originally filed specification by the Examiner did NOT find any specific basis for the recited limitation. The disclosure (including the specification, claims and sequence listing) as originally filed, does not contain an explicit recitation of the limitation. The closest support for such a limitation of is the disclosure of one species of a CYP26 inhibitor of R115866 (pg. 56). The disclosure of 1 specific species does not provide support for the full breadth of the genus of CYP26 inhibitors.
As noted by MPEP 608.04(a), new matter includes not only the addition of wholly unsupported subject matter, but may also include adding specific percentages or compounds after a broader original disclosure, or even the omission of a step from a method. In the instant case one skilled in the art would NOT consider the full breadth of the genus of activators of Hh signalling that have the function of “activates GLI transcription factors” or the full breadth of the genus of CYP26 inhibitors to be explicitly, implicitly, or inherently supported by Applicant’s disclosure.
Hence, there is insufficient written descriptions support for the instantly claimed limitation of and Applicant has not shown possession of the invention.
Response to Arguments
Applicant’s arguments, filed 16th, December, 2025, have been fully considered but are not found persuasive.
Applicant argues “Support for amended claims 1, 2, 4, 5, 14, 15, 17, 19, and 55 can be found in the original claims and as-filed specification” (pg. 7). Applicant argues “Support for new claims 56-58 can be found in the original claims and as-filed specification.” (pg. 7).
In response, the original claims and as-filed specification do not appear to provide support for the new limitation as discussed above.
Additionally, Applicant has not provided the specific location of support for this amendment. When filing an amendment an applicant should show support in the original disclosure for new or amended claims. See MPEP §§ 714.02 and 2163.06 ("Applicant should ... specifically point out the support for any amendments made to the disclosure.") The claims are new or amended claims, the support for the limitations is not apparent, and applicant has not pointed out where the limitations are supported and therefore the limitations appear to be new matter (see MPEP 2163 (I)).
Withdrawn Claim Rejections - 35 USC § 112(a)
Written Description
The rejection of claims 8, 10 and 13 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 as set forth in the previous office action is withdrawn in view of the cancellation of these claims.
The rejection of claims 1-5, 8, 10, 13-15, 17, 21-22, 25 and 55 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 as set forth in the previous office action is withdrawn in view of Applicant’s amendments and arguments of record.
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.
Claim 19 is 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 purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997).
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include a disclosure of a representative number of species to describe the complete structure of the claimed genus and/or disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof.
Scope of the Invention
In the instant case, the genera are:
retinoic acid analogues and functional analogues of activators of retinoic acid signaling (claim 19)
The broadest reasonable interpretation of the scope of this genus encompasses all possible “analogues” of retinoic acid signaling pathways that increase activation of a retinoic acid receptor.
The plain and ordinary meaning of an analogue is a structure that is similar to another and may have some overlapping properties. Therefore, the breadth of this genus encompasses structures that are similar to all possible activators of retinoic acid signaling pathways that increase activation of a retinoic acid receptor which includes structurally and functionally distinct members including but not necessarily limited to nucleic acids, proteins, and small molecules. Because the analogues may not retain all possible functions, this includes structurally and functionally distinct members including but not necessarily limited to nucleic acids, proteins, and small molecules that may or may not function to activate retinoic acid signaling as claimed.
Isomers of activators of retinoic acid signaling (claim 19)
The broadest reasonable interpretation of the scope of this genus encompasses all possible “isomers” of activators of retinoic acid signaling pathways that increase activation of a retinoic acid receptor.
An isomer is a compound with the same formula but a different arrangement of atoms and different properties. Therefore, the breadth of this genus encompasses structures that isomers to all possible activators of retinoic acid signaling pathways that increase activation of a retinoic acid receptor which includes structurally and functionally distinct members (isomers may be composed of the same formula, but they comprise a different structure because they have a different arrangement of the atoms which may result in a different function). Because isomers have distinct structures and functions, this includes structurally and functionally distinct members that may or may not function to activate retinoic acid signaling as claimed.
Disclosure of Structure and Disclosure of Species
Activators of Retinoic Acid Signaling
Regarding the activators of retinoic acid signaling and functional analogue or isomer of said activators, Applicant discloses the following 20 species structures:
Retinoic acid, particularly 9-cis-retinoic acid (9cRA), 13-cis-retinoic acid (13cRA), and all-trans-retinoic acid (ATRA) (pg. 7).
Retinoic acid, all-trans retinoic acid; AM 580; TTNPB; Ch 55;CD437; BMS961;BMS 753; AM 80; CD 2314; AC 261066; AC 55649; CD 1530;Adapalene; Tazarotenic Acid; Tazarotene; EC 19; EC23 (pg. 31).
Structure/Function Relationship
Regarding the activators of retinoic acid signaling, analogues, functional analogues or isomers of activators of retinoic acid signaling, as stated above (see scope of the Invention above), this encompasses distinct structures that have distinct functions mechanisms of action for the reasons stated above.
Regarding the analogues, functional analogues, and isomers, Applicant is directed to the art of Klein et al. (J Biol Chem. 1996 Sep 13;271(37):22692-6.; henceforth “Klein”). Klein evidences neutral antagonists AGN 192870 and 193840 (pg. 22694) and inverse antagonists AGN 193109 (Figure 2) of Retinoic Acid Receptors (see also Table 1). Klein evidences inverse agonists are ligands that are capable of repressing basal receptor activity in the absence of an agonist (abstract) and Klein evidences neutral antagonists do not affect the receptor equilibrium but are capable of competitive antagonism of both agonists and inverse agonists (pg. 22692). Therefore, the art of Klein evidences analogues, functional analogues or isomers of activators of retinoic acid signaling include neutral antagonists, which would not activate retinoic acid receptors, and inverse antagonists, which would repress the retinoic acid receptors, and these fall outside of the functional requirements of instant claims. Therefore, because the art evidences the structure/function relationship is not predictable because analogues, functional analogues or isomers of activators of retinoic acid signaling do not predictably exhibit the required function of activating a retinoic acid receptor, and Applicant has failed to provide a nexus to lead one of ordinary skill to which analogues, functional analogues or isomers of activators of retinoic acid signaling, one of ordinary skill would not be able to envision the requisite structural elements at the time of filing.
.
Written Description - Conclusion
Therefore, the examiner concludes there is insufficient written description support for the instantly claimed genera. Specifically, there is insufficient description of functional derivatives or isomers of activators of retinoic acid signaling pathway activators. The specification merely describes 20 specific species of retinoic acid signaling pathway activators, functional analogues or isomers of activators of retinoic acid signaling. 20 species does not represent the large genus of structurally and functionally diverse species of functional analogue or isomers of activators of retinoic acid signaling that activate a retinoic acid receptor discussed above.
Thus, in the face of an unpredictable art, one of ordinary skill in the art could not envision the requisite structural elements and the elements that could be modified from the disclosures of the application or art at the time of filing.
Response to Arguments
Applicant’s arguments, filed 16th, December, 2025, have been fully considered but are not found persuasive.
Applicant argues “Applicant notes that at least R115866 was also described in the specification” (pg. 8).
In response, the examiner had acknowledged that R115866 was also described in the specification. However, R115866 appears to work by inhibiting the metabolic activation of all -trans retinoic acid, which does not fall under the scope of the amended claims which requires the at least one activator of retinoic acid (RA) signalling increases activation of a retinoic acid receptor. To complete the art of record and rebut Applicant’s arguments, Applicant is directed to the art of Stoppie et al. (J Pharmacol Exp Ther. 2000 Apr;293(1):304-12.; henceforth “Stoppie”). Stoppie evidences R115866 as a potent, orally active inhibitor of RA metabolism (abstract).
The examiner notes that Applicant’s amendments have not overcome the written description issue with respect to isomers and functional analogues of activators of retinoic acid signaling. This aspect of the rejection is reapplied above as it applies to the amended claims. The arguments of record do not appear pertinent to these issues.
Withdrawn Claim Rejections - 35 USC § 112(a)
Scope of Enablement
The rejection of claims 1-3, 5, 14-15, 17, 19, 21-22, 25 and 55 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification did not enable the full scope of the claims is withdrawn in view of the Applicant’s amendments and arguments of record.
The rejection of claims 8, 10 and 13 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification did not enable the full scope of the claims is withdrawn in view of the cancellation of these claims.
Claim Rejections - 35 USC § 112(a)
Scope of Enablement
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.
Claim 4 is 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:
A method for differentiating pluripotent stem cells into ventral midbrain dopaminergic progenitor cells, the method comprising
contacting a plurality of pluripotent stem cells with at least one inhibitor of TGFβ/Activin-Nodal signaling and at least one inhibitor of bone morphogenetic protein (BMP) signaling from day 0 to day 7;
contacting the plurality of pluripotent stem cells with ATRA at a concentration of 200-400 nM from day 0 to day 2; contacting the plurality of pluripotent stem cells with 500 nM 9-cis RA, 13-cis RA or tazarotenic acid (TA) from day 0 to day 2; or contacting the plurality of pluripotent stem cells with EC23 at a concentration of 10-20 nM of from day 0 to day 1; and
contacting the plurality of pluripotent stem cells with SAG 1.3 at a concentration of 50 nM or more from day 0 to day 9;
to obtain a cell population comprising at least 50%, at least 60%, at least 70% or at least 80% of ventral midbrain dopaminergic progenitor cells.
does not reasonably provide enablement for:
all other culture conditions including but not necessarily limited to all possible timings, durations, concentrations of all possible
all other concentrations, timings, and durations of retinoic acid signaling activators that increase activation of a retinoic acid receptor to arrive at the claimed and required functional result of a cell population comprising at least 50%, at least 60%, at least 70% or at least 80% of ventral midbrain dopaminergic progenitor cells.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the method of the invention commensurate in scope with these claims.
Wands Factors
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
Breadth of the Claims
Instant claims encompass methods for differentiating stem cells into ventral midbrain
dopaminergic progenitor cells comprising contacting a plurality of stem cells with “an effective amount of at least one activator of retinoic acid (RA) signaling” that increases activation of a retinoic acid receptor
This encompasses:
all possible “activators of retinoic acid (RA) signaling” that increase activation of a retinoic acid receptor including but not necessarily limited to nucleic acids, proteins or small molecules and further encompasses all possible timings and durations of each of these within the 1-4 days duration of the claim.
Direction or Guidance Presented
While contemplating all possible “activators of retinoic acid (RA) signaling” that increase activation of a retinoic acid receptor as part of a method to cause differentiation of the stem
cells into a cell population comprising ventral midbrain dopaminergic progenitor cells, Applicant provides limited guidance on culture conditions that result in the claimed cell types (Example 1; Figure 1).
Present Working Examples
The elements of the present working examples considered pertinent to the instant scope of enablement issues are summarized below.
Example 1 (pg. 59-75)
Stem cells: human embryonic stem cells (hESCs) which are a type of pluripotent stem cells
activator of retinoic acid (RA) signaling: all-trans RA
Concentration: 200 nM
Timings: all-trans RA was applied the first 1, 2, 3 or 4 days of differentiation (RA1D, RA2D, RA3D, RA4D) (Fig. 1a)
Additional conditions: dSMADi treatment was included in all experiments (pg.62). This appears to be for a timeframe of 7 days and appears to overlap with all-trans RA treatment (see Figure 1a which is copied below).
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Results: in hPSC-cultures not exposed to RA (RAOD), NSCs acquired a FOXG1+/OTX2+/HOXA2-FB-like identity (Fig. 1h)
A similar FB-like character was observed in RA1D cultures, though the number of FOXG1+ cells was somewhat reduced (Fig. 1h; Figure 7d (Supplementary Fig. 1d)).
In RA2D cultures, FB markers were suppressed and NSCs instead expressed a FOXG1-/OTX2+/HOXA2- MB-like character (Fig. 1h; Figure 7d (Supplementary Fig. 1d)).
In RA3D and RA4D cultures, NSCs acquired a FOXG1-/OTX2-/HOXA2+/ HOXB4- rostral HB and FOXG1-/OTX2-/HOXA2+/HOXB4+ caudal HB identities, respectively (Fig. 1h).
The specification states “These data suggest that a 48-hour RA-pulse suppresses FB fate and imposes a MB-like identity to hPSC-derived NSCs (Fig. 1i).”
Next, SHH signaling was activated to impose a ventral identity to NSCs.
Conditions: cultures were treated with Smoothened agonist SAG25 between 0-9 DDC (see Figure 2 a; copied below)
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Results: At 9 DDC, NSCs generated in SAG-only or RA1D+SAG conditions expressed the FB- specific markers FOXG1, SIX3, SIX6, and LHX2 (Fig. 2b) and the ventral marker NKX2.1 (Fig. 2a, b) which is a selective marker for the ventral telencephalon and diencephalon.
In RA2D+SAG cultures, FB markers were suppressed and NSCs adopted a LMX1A+/LMX1B+/FOXA2+/OTX2+ identity characteristic of vMB mDA neuron progenitors (Fig. 2a,b,d).
In RA3D+SAG or RA4D+SAG cultures, cells expressed HOX genes and the ventral markers NKX2.2, PHOX2B, NKX6.1, and NKX6.2 typical of cranial motor neuron (MN) progenitors of the HB28 (Fig. 2a, b, d; and data not shown).
Applicant states these data show: first, that increases in the duration of RA exposure imposes progressively more caudal regional brain identities (FB->MB->HB) of hPSC-derived NSCs (Fig. 1i), and
second, when combined with activation of the SHH pathway, treatment with RA for 48h appears sufficient to impose a LMX1A+/FOXA2+/OTX2+ vMB-like identity to NSCs (Figure 8e (Supplementary Fig. 2e)).
Applicant states Effective induction of a vMB NSC identity required the 48 hour RA-pulse to be initiated between 0-2 DDC (Figure 8b (Supplementary Fig. 2b)) and SAG treatment to start at 0 or 1 DDC at a concentration > 50 nM (Figure 8c,d (Supplementary Fig. 2c,d)).
Similar results were attained with two hESC-lines and two hiPSC-lines (Figure 8e (Supplementary Fig. 2e)).
To determine the sensitivity of the differentiation procedure to altered concentrations of RA, Applicants cultured cells in RA2D+SAG-conditions and altered the concentration of RA in the range of 100-800 nM and analyzed the identity of NSCs at 9 DDC. In cultures exposed to 200-400 nM RA, the vast majority of NSCs expressed a LMX1A+/NKX2.1- vMB-identity and few cells expressed a diencephalic LMX1A+/NKX2.1+ identity or NKX2.2 (Fig. 3a,c).
When RA concentration was reduced to 100 nM or increased to 800 nM RA, LMX1A+/NKX2.1- NSCs were generated but at lower numbers (Fig. 3c).
This indicates the required concentration range of all trans Retinoic acid is 200-400 nM when the majority of the population is required to be vMB.
Exposure of cells to 500 nM of 9-cis RA, 13-cis RA and the xenobiotic RA-analogue tazarotenic acid (TA) analogues for 48-hours mimicked the patterning activity of all-trans RA by imposing a LMX1A+/NKX2.1- vMB identity (Fig. 3h; Figure 9b (Supplementary Fig. 3b)),
EC23 could induce LMX1A*/NKX2.1- vMB cells, but this required a 20-fold reduction in concentration and treatment of cells only for 24 hours (Figure 9c (Supplementary Fig. 3c)).
Applicant states “Together, these data establish that the AP-patterning output in response to timed RA exposure is critically reliant on the RA concentration-dependent activation of CYP26A1 in responding hPSCs” (pg. 66).
Evidence of the Specification
Applicant is directed to Applicant’s own specification, which evidences specific concentrations, durations, components and timings that are required to obtain the claimed ventral midbrain dopaminergic progenitor cells.
Specific Activators of RA signaling
The instant specification evidences specific small molecules activators of retinoic acid signaling of all-trans RA, 9-cis RA, 13-cis RA and the xenobiotic RA-analogue tazarotenic acid (TA) analogues, and EC23 are required (Example 1).
Therefore, because the effects of different Specific Activators of RA signaling are not predictable, Applicant is not enabled for all activators of RA signaling that activate a retinoic acid receptor.
Specific Timings and Durations of Activators of RA signaling
Regarding the timings of Application of Retinoic acid, Applicant’s own specification evidences timings of activators of retinoic acid signaling are unpredictable. Specifically, the specification states “The duration of RA exposure is a key determinant for a switch-like conversion of hPSCs into neural stem cells expressing a mesencephalic identity” (pg. 59).
The instant specification evidences timings of the specific small molecules activators of retinoic acid signaling of all-trans RA, 9-cis RA, 13-cis RA and the xenobiotic RA-analogue tazarotenic acid (TA) analogues as a 48-hour pulse initiated between 0-2 DDC is required (Example 1).
The instant specification evidences timings of the specific small molecules activators of retinoic acid signaling of EC32 requires treatment for only 24 hours (Example 1).
Therefore, because the effects of timings of RA signaling are not predicable, Applicant is not enabled for all timings and durations of RA signaling.
Specific Concentrations of Activators of RA signaling
The instant specification evidences the required concentration range of the retinoic signaling activator all Trans RA of 200-400 nM is required for the majority of the population to be ventral midbrain dopaminergic progenitor cells.
The instant specification evidences the required concentration range of the retinoic signaling activators 9-cis RA, 13-cis RA and the xenobiotic RA-analogue tazarotenic acid (TA) analogues of 500 nM is required for the majority of the population to be ventral midbrain dopaminergic progenitor cell (Example 1).
The instant specification evidences the required concentration range of the retinoic signaling activator EC23 required a 20-fold reduction in concentration and treatment of cells only for 24 hours (Figure 9c (Supplementary Fig. 3c))for the majority of the population to be ventral midbrain dopaminergic progenitor cells (Example 1).
Therefore, because the effects of different Specific concentrations of Activators of RA signaling are not predicable, Applicant is not enabled for concentrations of all activators of RA signaling.
Unpredictability of the Art and the Quantity of Experimentation Necessary
As the evidence in the instant specification demonstrate, the obstacles that hinder the use of the claimed method are not easy tasks to be done or solely routine experimentation to enabled particular embodiments of the claimed method. The type of experimentation would require new methodologies. This level of experimentation goes beyond what would be routine optimization know at the time of filing. As such, the amount of experimentation would be undue.
The physiological art is recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112(a) requires: “That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.” Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maize!.). In view of the foregoing, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to practice the instant broadly claimed invention.
Scope of Enablement - Conclusion
In conclusion, the breadth of the claims lack enablement because the specification provides limited working examples with specific concentrations of specific types of small molecule activators of retinoic acid signaling and specific timings and durations of the activators to arrive at the claimed functional result of a cell population comprising at least 50%, at least 60%, at least 70% or at least 80% of ventral midbrain dopaminergic progenitor cells. The state of the art at the time of effective filing fail to provide specific guidance that supplement to shortcomings of the specification and the instant specification further evidences that the breadth of claims cannot predictably be performed. Further, a great deal of new methodology would need to be developed to enable the full breadth of the claims and this level of experimentation is undue.
Examiner’s Remark
The Examiner notes that Applicant’s amendments and arguments of record have overcome some, but not all issues presented with respect to the rejection of record under 35 U.S.C. 112a because the full scope of the claims was not enabled with respect to claim 4 specifically. These are addressed below.
Response to Arguments
Applicant’s arguments, filed 16th, December, 2025, have been fully considered but are not found persuasive.
Applicant argues “one of skill in the art could determine concentration ranges without undue experimentation” (pg. 16). Applicant argues the claim requires RAR activation for 1-4 days and the specification provides working concentration ranges and cellular readouts (OCT4 suppression, SOX1/PAX6 induction, regional markers) enabling a skilled person to test exposure for any RAR agonist within the claim without undue experimentation. Applicant submits that routine titration is not undue experimentation” (pg. 16). Applicant argues “it would be clear to one of skill in the art how to determine if other activators of RA signalling are encompassed by the claims since it would be routine to determine if a given compound activates the RA receptor using assays known in the art, and/or those described on page 7 lines 16-20 of the application as filed” (pg. 17).
In response, the rejection of record under 35 U.S.C. 112a due to scope of enablement still applies to amended claim 4 because the claim requires the functional result that the obtained cell population comprises at least 50%, at least 60%, at least 70%, at least 80% ventral midbrain
dopaminergic progenitor cells at least after 7 days after first contacting said plurality of stem cells with the at least one activator of Retinoic Acid (RA) signalling. As set forth in the ground of rejection above, the instant specification evidences that the specific durations and timings of specific retinoic acid signalling activators do not predictably result in a majority of ventral midbrain dopaminergic progenitor cells. Therefore, this functional result appears to be unpredictable and would require undue experimentation to achieve.
Additionally, in order to complete the art of record and rebut Applicant’s arguments, Applicant is directed to the art of Trown et al. (Cancer Res. 1980 Feb;40(2):212-20.; henceforth “Trown”). Trown evidences activators of retinoic acid signaling that vastly different potencies (see IC50s on table 1). Therefore, because different activators have drastically different potencies, these different activators of retinoic acid signaling would appear to require drastically different amounts to achieve the required the functional result that the obtained cell population comprises at least 50%, at least 60%, at least 70%, at least 80% ventral midbrain dopaminergic progenitor cells at least after 7 days after first contacting said plurality of stem cells with the at least one activator of Retinoic Acid (RA) signaling and this does not appear to be predictable from the structure of the activator.
Withdrawn Claim Rejections - 35 USC § 112(b)
The rejection of claims 2, 4-5 and 17 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
New 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 19 and 56 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 19 recites the at least one activator of Retinoic Acid (RA) signalling can be “a retinoic acid analogue” or a “functional analogue or isomer thereof” of a retinoic acid analogue; a RARα agonist; a RARβ agonist; a RARγ agonist; an RXR agonist, a CYP26 inhibitor, retinoic acid, all-trans retinoic acid (ATRA); AM 580; TTNPB; Ch 55; CD437; BMS 961; BMS 753; AM 80; CD 2314; AC 261066; AC 55649; CD 1530; Adapalene; Tazarotenic Acid; Tazarotene; EC 19; EC23” which is broader than the “activator of Retinoic Acid (RA) signalling” as recited in claim 1, upon which claim 19 depends, because claim 1 requires “the at least one activator of retinoic acid (RA) signalling increases activation of a retinoic acid receptor” which is more specific than the “retinoic acid analogue” or a “functional analogue or isomer thereof” of the recited substances because not all retinoic acid analogues, or functional analogues or isomers of the recited compounds have the function of increasing activation of a retinoic acid receptor.”
Regarding claim 19, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). Note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu, 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), as to where broad language is followed by "such as" and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Note also, for example, the decisions of Ex parte Steigewald, 131 USPQ 74 (Bd. App. 1961); Ex parte Hall, 83 USPQ 38 (Bd. App. 1948); and Ex parte Hasche, 86 USPQ 481 (Bd. App. 1949).
Claim 19 recites “a CYP26 inhibitor” as an option of the at least one activator of Retinoic Acid (RA) signalling. However, claim 1, upon which claim 19 depends, requires “the at least one activator of retinoic acid (RA) signalling increases activation of a retinoic acid receptor.” Because a CYP26 inhibitor does not have the function of increasing activation of a retinoic acid receptor, it is unclear how this embodiment can further limit claim 1, as it appears to be excluded from the scope of claim 1 and therefore the metes and bounds of this term in claim 19 are unclear.
Claim 56 recites exemplary language (“such as”). Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim (see MPEP 2173.05(d)).
Claim 56 is vague and indefinite in the use of parenthesis, since it is unclear whether the parenthetical material is or is not intended to be part of the claim. Specifically, it is unclear whether “(Hh-1.3)” is or is not intended to be part of the claim.
New Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 19 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 19 recites the at least one activator of Retinoic Acid (RA) signalling can be “a retinoic acid analogue” or a “functional analogue or isomer thereof” of a retinoic acid analogue; a RARα agonist; a RARβ agonist; a RARγ agonist; an RXR agonist, a CYP26 inhibitor, retinoic acid, all-trans retinoic acid (ATRA); AM 580; TTNPB; Ch 55; CD437; BMS 961; BMS 753; AM 80; CD 2314; AC 261066; AC 55649; CD 1530; Adapalene; Tazarotenic Acid; Tazarotene; EC 19; EC23” which is broader than the “activator of Retinoic Acid (RA) signalling” as recited in claim 1, upon which claim 19 depends, because claim 1 requires “the at least one activator of retinoic acid (RA) signalling increases activation of a retinoic acid receptor” which is more specific than the “retinoic acid analogue” or a “functional analogue or isomer thereof” of the recited substances because not all retinoic acid analogues, or functional analogues or isomers of the recited compounds have the function of increasing activation of a retinoic acid receptor.” Because claim 19 recites embodiments that are broader than the claim upon which it depends, it cannot further limit those embodiments.
Claim 19 recites “a CYP26 inhibitor” as an option of the at least one activator of Retinoic Acid (RA) signalling. However, claim 1, upon which claim 19 depends, requires “the at least one activator of retinoic acid (RA) signalling increases activation of a retinoic acid receptor.” Because a CYP26 inhibitor does not have the function of increasing activation of a retinoic acid receptor, it appears to be excluded from the scope of claim 1 and therefore this embodiment of claim 19 cannot further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Withdrawn Claim Rejections - 35 USC § 112
Improper Markush
Claim 19 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of “a retinoic acid analogue; a RARα agonist; a RARβ agonist; a RARγ agonist; an RXR agonist, a CYP26 inhibitor, retinoic acid, all-trans retinoic acid (ATRA); AM 580; TTNPB; Ch 55; CD437; BMS 961; BMS 753; AM 80; CD 2314; AC 261066; AC 55649; CD 1530; Adapalene; Tazarotenic Acid; Tazarotene; EC 19; EC23; or a functional analogue or isomer thereof” is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: The grouping lists members that do not share a single structural similarity because it recites structurally distinct members.
Specifically, while “a retinoic acid analogue; a RARα agonist; a RARβ agonist; a RARγ agonist; an RXR agonist, retinoic acid, all-trans retinoic acid (ATRA); AM 580; TTNPB; Ch 55; CD437; BMS 961; BMS 753; AM 80; CD 2314; AC 261066; AC 55649; CD 1530; Adapalene; Tazarotenic Acid; Tazarotene; EC 19; EC23” and functional derivatives or analogs of these appear to be part of an art-recognized class of retinoic acid signaling activators that act on retinoic acid receptors to activate them, a “CYP26 inhibitor” appears to be structurally and functionally distinct and makes the Markush group improper.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Response to Arguments
Applicant’s arguments, filed 16th, December, 2025, have been fully considered but are not found persuasive.
Applicant argues “Because they are functional equivalents, the Markush group is proper” (pg. 18).
In response, Applicant is directed to MPEP 2117 (II) which states that a Markush claim contains an "improper Markush grouping" if either: (1) the members of the Markush group do not share a "single structural similarity" or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)). In the instant case, CYP26 does not share a single structural similarity with a retinoic acid analogue; a RARα agonist; a RARβ agonist; a RARγ agonist; an RXR agonist, retinoic acid, all-trans retinoic acid (ATRA); AM 580; TTNPB; Ch 55; CD437; BMS 961; BMS 753; AM 80; CD 2314; AC 261066; AC 55649; CD 1530; Adapalene; Tazarotenic Acid; Tazarotene; EC 19; EC23” and functional derivatives or analogs of these and therefore the Markush group is improper.
Withdrawn Claim Rejections - 35 USC § 102
The rejection of claims 1-5, 8, 13-14, 17, 19, 21-22, 25 and 55 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cooper et al. (WO-2011/130675-A2; see IDS filed 24th, April, 2023; henceforth “Cooper”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
The rejection of claims 8 and 13 under 35 U.S.C. 102(a)(1) as being anticipated by Cooper et al. (WO-2011/130675-A2; see IDS filed 24th, April, 2023; henceforth “Cooper”) as set forth in the previous office action are withdrawn in view of the cancellation of these claims
The rejection of claims 8, 10 and 13 under 35 U.S.C. 102(a)(1) as being anticipated by Ashton et al. (US-2019/0024046-A1; henceforth “Ashton”) as set forth in the previous office action are withdrawn in view of the cancellation of these claims
Claim Rejections - 35 USC § 102
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.
Claims 1-5, 14, 17, 19, 21-22 and 56-58 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ashton et al. (US-2019/0024046-A1; henceforth “Ashton”).
Regarding claim 1, Ashton discloses a method for differentiating stem cells (human pluripotent stem cells) into neural rosettes (“singular rosette structure having regional neural progenitor phenotypes” abstract), the method comprising contacting a plurality of stem cells with an effective amount of at least one activator of retinoic acid (RA) signaling (“in some embodiments, a retinoic acid receptor agonist is also included to facilitate neural differentiation into certain neuronal lineages depending on the concentration of retinoid used” para. [0079]), and culturing the stem cells under conditions sufficient to cause differentiation of the stem cells into a cell population comprising ventral midbrain dopaminergic progenitor cells (“singular rosette structure having regional neural progenitor phenotypes”; abstract); wherein the culturing comprises dual SMAD inhibition (TGFβ signaling antagonist and a BMP signaling antagonist; para. [0080]) wherein the first SMAD inhibitor is one or more inhibitor of TGFB/Activin Nodal signalling (TGFβ signaling antagonist para. [0080]) and the second SMAD inhibitor is one or more inhibitor of BMP signalling (BMP signaling antagonist para. [0080]), and contacting the stem cells with at least one activator of Hedgehog (Hh) signalling (“exposing the seeded cells to RA and Sonic Hedgehog (SHH) or a SHH signaling agonist for about 1 to about 5 days” para. [0006, 0054])
wherein the stem cells are contacted with the activator of retinoic acid (RA) signalling for 1-4 days(“exposing the seeded cells to RA and Sonic Hedgehog (SHH) or a SHH signaling agonist for about 1 to about 5 days” para. [0006, 0054]));
wherein the stem cells are pluripotent cells (human pluripotent stem cells).
Regarding claim 1, concerning the wherein clause which recites “wherein the at least one activator of Hh signalling increases smoothened signalling,” Ashton discloses the activator of Hh signalling is Sonic Hedgehog or Purmorphamine (para. [0006, 0016, 0054, 0056, 0123, 0143]; Claim 13), which both increase smoothened signaling.
Regarding claim 1, concerning the wherein clause which recites “wherein the at least one activator of retinoic acid (RA) signalling increases activation of a retinoic acid receptor,” Ashton discloses the activator of retinoic acid (RA) signalling is all-trans retinoic acid (ATRA) (para. [0079]), which increases activation of a retinoic acid receptor.
Regarding the preamble of “differentiating stem cells into ventral midbrain dopaminergic progenitor cells” of claim 1, the preamble merely states the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, and therefore the preamble is not considered a limitation and is of no significance to claim construction (see MPEP 2111.02) See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation"). Furthermore, Ashton discloses the active method steps of the instantly claimed method and the result of differentiating stem cells into ventral midbrain dopaminergic progenitor cells would inherently follow the recitation of the disclosed steps. Lastly, Ashton discloses the neural rosettes can have ventral patterning (“Rosette formation and ventralization” para. [0124]; see also para. [0097, 0107, 0122-123, 0135, 0143) and therefore the method disclosed by Ashton results in differentiation of the stem cells to ventral midbrain dopaminergic progenitor cells.
Regarding claim 2, further to the discussion of claim 1 above, it is noted that the wherein clause does not recite any additional active method steps, but simply states an inherent property of the claimed activator of retinoic acid (RA) signaling (“effective to specify ventral midbrain identity to neural stem cells derived from the pluripotent stem cells”). Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."). See also MPEP 2111.04 that a “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure” and a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.”
Furthermore, regarding claim 2, Ashton discloses the at least one activator of retinoic acid (RA) signaling is All-Trans Retinoic Acid (ATRA). Being “effective to specify ventral midbrain identity to neural stem cells derived from the pluripotent stem cells” is an inherent property of the ATRA disclosed by Ashton.
Regarding claims 3-5, further to the discussion of claim 1 above, it noted that the wherein clauses do not recite any additional active method steps, but simply state a characterization or conclusion of the results of process step positively recited. Therefore, the "wherein" clauses are not considered to further limit the method defined by the claims and have not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) See also MPEP 2111.04.
Furthermore, regarding claims 3-5, Ashton discloses the active method steps of the instantly claimed method and therefore the results of “the ventral midbrain progenitor cells express FOXA2 and LMX1A” (instant claim 3), “the cell population comprises at least 50%, at least 60%, at least 70%, or at least 80% ventral midbrain dopaminergic progenitor cells” (instant claims 4-5) after “at least after 7 days after first contacting said cell population with the at least one activator of Retinoic Acid (RA) signaling” (instant claim 5) would inherently follow the recitation of the disclosed steps.
Regarding claim 14, further to the discussion of claim 1 above, as stated above, Ashton discloses exposing the seeded cells to RA and Sonic Hedgehog (SHH) or a SHH signaling agonist for about 5 days (para. [0006, 0054])). Therefore, the activator of retinoic acid signaling is not present in the media after about 5 days and is not present in an effective amount after the disclosed “about 5 days.” It is noted that in the absence of a special definition of “about,” the disclosed “about 5 days” is encompassed by the breadth of the claimed “about 4 days.”
Regarding claim 17, further to the discussion of claim 1 above, the method disclosed by Ashton includes a specific embodiment that has a specific step of exposing the seeded cells to RA and Sonic Hedgehog (SHH) or a SHH signaling agonist for about 1 to about 5 days (para. [0006, 0054])), and includes an activator of wingless (Wnt) signaling as an optional alternative in this step (“In some cases, the method further comprises transiently exposing cells on the micropatterned substrate to an activator of Wnt/β-catenin signaling about 24-72 hours after plating onto the micropatterned substrate” para. [0006]). Therefore, the option that does not include the Wnt activator specifically disclosed by Ashton does not comprise a) an activator of wingless (Wnt) signaling simultaneously with the at least one activator of retinoic acid (RA) signaling.
Regarding claims 19 and 21, further to the discussion of claim 1 above, Ashton disclose the at least one activator of Retinoic Acid (RA) signaling is all-trans retinoic acid (ATRA) (para. [0079]).
Regarding claim 22, further to the discussion of claim 1 above, the retinoic acid signaling activators taught by Ashton are applied to cell culture media and are therefore derived from an exogenous source.
Regarding claim 56, further to the discussion of claim 1 above, Ashton discloses the activator of Hh signaling is Sonic Hedgehog or Purmorphamine (para. [0006, 0016, 0054, 0056, 0123, 0143]; Claim 13).
Regarding claim 57, further to the discussion of claim 1 above, Ashton discloses the at least one inhibitor of TGFβ/Activin-Nodal signalling is SB431542 (para. [0080]).
Regarding claim 58, further to the discussion of claim 1 above, Ashton discloses the at least one inhibitor of BMP signalling is Noggin (para. [0080]).
Accordingly, Ashton anticipates instant claims.
Response to Arguments
Applicant’s arguments, filed 16th, December, 2025, have been fully considered but are not found persuasive.
Applicant argues “paragraph [0080] of Ashton explicitly states that neural induction is carried out " ... in the substantial absence of embryoid bodies, a TGFβ superfamily agonist, a TGFβ signalling antagonist, or a bone morphogenetic protein (BMP) signalling antagonist" (emphasis added). These antagonists are SMAD inhibitors, so the disclosure of Ashton confirms that the core method achieves neural differentiation without SMAD inhibitors and therefore without dual SMAD inhibition (dSMADi). This is reinforced later in paragraph [0110] of Ashton, which describes the E6 protocol producing neuroepithelial cells "... In six days and without the use of SMAD inhibitors ... ". Accordingly, Ashton teaches away from dual SMAD inhibition as currently claimed.” (pg. 22).
In response, the reference of Ashton is applied under 35 U.S.C. 102 above and meets the limitations of instant claims for the reasons set forth in the rejection of record above. Ashton clearly discloses an embodiment of dual SMAD inhibition in para [0080] as set forth in the rejection of record above.
Regarding Applicant’s argument that Ashton teaches away, this is not a consideration for 35 U.S.C. 102. Furthermore, Applicant is directed to MPEP 2123 (I) which states "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). In the instant case, Ashton clearly discloses the limitations of the claimed invention for the reasons set forth above.
Applicant is additionally directed to MPEP 2123 (II) which states that disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). Therefore in the instant case, the disclosure of a preferred embodiment of without SMAD inhibitors does not teach away from the clearly disclosed embodiment which includes dual SMAD inhibitors.
Applicant argues “Ashton describes protocols that consistently generate forebrain neural stem cells (PAX6+/QTX2+) or ventral spinal cord progenitors (Nkx6.I+/Qlig2+ pMNs, often HoxB4+), as confirmed by immunocytochemistry, qPCR, and its discussion of "rosette formation and ventralization" for spinal tissues. Ashton fails to teach induction of ventral midbrain dopaminergic progenitors or the characteristic floor-plate marker set including LMX1A and FOXA2 as currently claimed.” (pg. 22).
In response, although Ashton is silent to whether the cells express forkhead box protein A2 (FOXA2) and LIM homeobox transcription factor 1 alpha (LMX1A) (as claimed in instant claim 3), because Ashton discloses all the active method steps of the instantly claimed method, the result of expression of FOXA2 and LMX1A would inherently follow the recitation of the disclosed steps. Applicant is remined that Integra Life Sciences I Ltd. v. Merck KGaA, 50 USPQ2d 1846 (DC SCalif, 1999) held that a reference teaching a process may anticipate claims drawn to a method comprising the same process steps, despite the recitation of a different intended use in the preamble or the later discovery of a particular property of one of the starting materials or end products.
Withdrawn Claim Rejections - 35 USC § 103
The rejection of claim 10 under 35 U.S.C. 103 as being unpatentable over Cooper et al. (WO-2011/130675-A2; see IDS filed 24th, April, 2023; henceforth “Cooper”) in view of Chambers et al. (Nat Biotechnol . 2009 Mar;27(3):275-80. Epub 2009 Mar 1.; see IDS filed 21st, August, 2023; henceforth “Chambers”) as set forth in the previous office action is withdrawn in view of the cancellation of this claim.
The rejection of claim 15 under 35 U.S.C. 103 as being unpatentable over Cooper et al. (WO-2011/130675-A2; see IDS filed 24th, April, 2023; henceforth “Cooper”) in view of Chambers et al. (Nat Biotechnol . 2009 Mar;27(3):275-80. Epub 2009 Mar 1.; see IDS filed 21st, August, 2023; henceforth “Chambers”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
New 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.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Ashton et al. (US-2019/0024046-A1; henceforth “Ashton”) in view of Chambers et al. (Nat Biotechnol . 2009 Mar;27(3):275-80. Epub 2009 Mar 1.; see IDS filed 21st, August, 2023; henceforth “Chambers”).
The teachings of Ashton above are hereby incorporated in their entirety.
Regarding claim 15, further to the discussion of claim 1 above, Ashton teaches the stem cells are contacted with the at least one activator of Hedgehog (Hh) signaling simultaneously with the at least one activator of retinoic acid (RA) signaling (“about 24-72 hours after seeding cells onto the micro patterned substrate, exposing the seeded cells to RA and Sonic Hedgehog (SHH) or a SHH signaling agonist for about 1 to about 5 days” para. [0006]).
However, regarding claim 15, although Ashton teaches contacting with the at least one inhibitor of TGFβ/Activin-Nodal signaling, and the at least one inhibitor of bone morphogenetic protein (BMP) signaling (see claim 1 rejection above and para. [0080] of Ashton), Ashton is silent to performing this step at simultaneously with contacting the cells with the activator of Hedgehog (Hh) signalling and the activator of retinoic acid (RA) signalling.
Nevertheless, regarding claim 15, Chambers teaches an active method step of contacting pluripotent stem cells with an inhibitor of bone morphogenetic protein (BMP) signaling (Noggin) and an inhibitor of TGFβ/Activin-Nodal signaling (SB431542) (dual inhibition of SMAD signaling; abstract; Figure 2; pg. 279 col. 2 2nd para. “Neural induction”) to induce rapid and complete neural conversion of pluripotent stem cells (abstract). Chambers teaches including the inhibitor of TGFβ/Activin-Nodal signaling from day 0 to day 5 (Figure 2 “Neuralization of hES cells by dual- SMAD inhibition permits a pre-rosette, neural stem cell with dopaminergic and motoneuronal potential”).
Therefore, regarding claim 15, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method of Ashton, and combine the known prior art element of the inhibitor of TGFβ/Activin-Nodal signaling of Chambers from days 0 to 5 to obtain the predictable result of improved neural conversation of the pluripotent stem cells in the method of Ashton. One of ordinary skill would have been motivated to do so a taught by Chambers to improve the method of Cooper by inducing rapid and uniform neural conversion of pluripotent cells, and allow for the derivation of relevant neuron subtypes after shorter differentiation period (pg. 279 col. 1 3rd para.). Including the inhibitor of TGFβ/Activin-Nodal signaling of Chambers from days 0 to 5 would be simultaneous with the activator of Hedgehog (Hh) signaling and the activator of retinoic acid signaling of Ashton (see “exposing the seeded cells to RA and Sonic Hedgehog (SHH) or a SHH signaling agonist for about 1 to about 5 days” para. [0006, 0054])) Regarding the reasonable expectation of success, Chambers evidences including the inhibitor of TGFβ/Activin-Nodal signaling from days 0 to 5 permits a pre-rosette, neural stem cell with dopaminergic potential (Figure 2).
Hence, the claimed invention as a whole was prima facie obvious.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Ashton et al. (US-2019/0024046-A1; henceforth “Ashton”) in view of Cooper et al. (WO-2011/130675-A2; see IDS filed 24th, April, 2023; henceforth “Cooper”).
The teachings of Ashton above are hereby incorporated in their entirety.
Regarding claim 25, further to the discussion of claim 1 above, Ashton is silent to a step of further differentiating the population comprising ventral midbrain dopaminergic progenitor cells into mesencephalic dopaminergic neurons.
Nevertheless, regarding claim 25, Cooper teaches a step of further differentiating a population comprising ventral midbrain dopaminergic progenitor cells into mesencephalic dopaminergic neurons (SN-A9 dopaminergic neurons para. [0009, 0011-0013, 0020, 0058, 0063, 0082-0084, 0086, 0091]; Example 2; claim 21). Cooper teaches the SN-A9 mesencephalic dopaminergic neurons can be used in a methods of treating neurodegenerative diseases, such as Parkinson’s Disease, by transplanting these dopaminergic neurons into the brain of the patient (para. [0063]).
Therefore, regarding claim 25, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method of Ashton, and combine the known prior art element of the step of further differentiating a population comprising ventral midbrain dopaminergic progenitor cells into SN-A9 mesencephalic dopaminergic neurons of Cooper to obtain the predictable result of a method for obtaining SN-A9 mesencephalic dopaminergic neurons. One of ordinary skill would have been motivated to do so as taught by Cooper to obtain SN-A9 dopaminergic neurons treat neurodegenerative diseases, such as Parkinson’s Disease, by transplanting these dopaminergic neurons into the brain of the patient (para. [0063]). Regarding the reasonable expectation of success, Cooper evidences a method step of further differentiating a population comprising ventral midbrain dopaminergic progenitor cells into mesencephalic dopaminergic neurons (SN-A9 dopaminergic neurons para. [0009, 0011-0013, 0020, 0058, 0063, 0082-0084, 0086, 0091]; Example 2; claim 21).
Regarding claim 55, further to the discussion of claim 1 above, although Ashton teaches contacting the cells with an activator of wingless (Wnt) signaling (para. [0006, 0008, 0016, 0054, 0056, 0067, 0070-0071, 0122-0124, 0143]; claims 12 and 24), Ashton is silent to the specific timing of contacting the plurality of stem cells with an activator of wingless (Wnt) signaling after the stem cells have been contacted with the at least one activator of retinoic acid (RA) signaling.
Nevertheless, regarding claim 55, Cooper teaches a method step of contacting plurality of stem cells with an activator of wingless (Wnt) signaling after the stem cells have been contacted with the at least one activator of retinoic acid (RA) signaling as part of a method for generating dopaminergic neurons (“the pluripotent stem cells are cultured in the presence of retinoic acid alone for a period of time and the SHH protein, WNT1 protein, and the FGF8A protein are applied to the cells later without removal of the retinoic acid” para. [0014]; see also para. [0009, 0011-0014, 0016-0017, 0020, 0036, 0045, 0048, 0058-0059, 0062-0063, 0074, 0086, 0089]; Example 1; claims 2, 22, 29, 35) to direct the fate of PS cells towards dopaminergic neurons (para. [0058]).
Therefore, regarding claim 55, it would have been obvious to a person of ordinary skill in the art before the effective filing date the claimed invention to practice the method of Ashton, and combine the known prior art element of the method step of contacting plurality of stem cells with an activator of wingless (Wnt) signaling after the stem cells have been contacted with the at least one activator of retinoic acid (RA) signaling of Cooper to obtain the predictable result of a method for generating dopaminergic neurons. One of ordinary skill would have been motivated to do so because Cooper teaches this as an effective timing of signaling after the stem cells have been contacted with the at least one activator of retinoic acid (RA) signaling to direct the fate of PS cells towards dopaminergic neurons (para. [0058]) for generating dopaminergic neurons. Regarding the reasonable expectation of success, Cooper evidences a method step of contacting plurality of stem cells with an activator of wingless (Wnt) signaling after the stem cells have been contacted with the at least one activator of retinoic acid (RA) signaling as part of a method for generating dopaminergic neurons (“the pluripotent stem cells are cultured in the presence of retinoic acid alone for a period of time and the SHH protein, WNT1 protein, and the FGF8A protein are applied to the cells later without removal of the retinoic acid” para. [0014]; see also para. [0009, 0011-0014, 0016-0017, 0020, 0036, 0045, 0048, 0058-0059, 0062-0063, 0074, 0086, 0089]; Example 1; claims 2, 22, 29, 35) to direct the fate of PS cells towards dopaminergic neurons (para. [0058]).
Conclusion
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.
No claim is allowable.
Correspondence
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632 /VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632