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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/11/2026 has been entered.
Status of the Claims
Claims 1-22 are pending.
Claims 16-17 and 21-22 are newly amended.
Claims 1-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election is treated as having been made without traverse in the reply filed on 10/14/2022.
Claims 16-22 have been examined on their merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn.
The rejection of claims 16-21 under 35 U.S.C. 103 as being unpatentable over Fedele et al. (Nature Scientific Reports, 2017, on IDS 04/21/2021, previously) in view of Wang et al. (Stem Cell Research & Therapy, 2015), Thorsten et al. (NeuroReport, 2006, previously cited), Jeon et al. (Stem Cells, 2018, previously cited), and Shim et al. (WO 2015/119575 A2, 2015, previously cited) is withdrawn upon reconsideration of the claim. However, a new grounds of rejection is made over Fedele et al. (Nature Scientific Reports, 2017, on IDS 04/21/2021, previously cited), etc., as discussed below.
Claim Interpretation
In regards to a chemically defined, serum-free, and xenogeneic material-free cell culture, in regards to a chemically defined medium, the specification states, “The terms ‘chemically defined medium’ and ‘chemically defined culture medium’ are used interchangeably and refer to a culture medium containing formulations of fully disclosed or identifiable ingredients, the precise quantities of which are known or identifiable and can be controlled individually. As such, a culture medium is not chemically defined if (1) the chemical and structural identity of all medium ingredients is not known, (2) the medium contains unknown quantities of any ingredients, or (3) both” (paragraph [0042]).
In regards to a serum-free medium, the specification states, “the term ‘serum-free’ refers to cell culture materials that are free of or substantially free of serum obtained from animal (e.g., fetal bovine) blood” (paragraph [0042]).
However, continuing, the specification also states, and in regards to xenogeneic material-free cell culture media, “In general, culturing cells or tissues in the absence of animal-derived materials (i.e., under conditions free of xenogeneic material) reduces or eliminates the potential for cross-species viral or prion transmission “ (paragraph [0042]).
Therefore, while a serum-free medium could only require that the medium is substantially free of serum, because it is also xenogeneic material-free (meaning, under conditions free of xenogeneic material), taken together, the claim has been interpreted as disallowing serum (which derives from animals) entirely (and thus is “free” not “substantially free” of serum).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis 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 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 16-20 are rejected under 35 U.S.C. 103 as being unpatentable over Fedele et al. (Nature Scientific Reports, 2017, on IDS 04/21/2021, previously cited) in view Swistowski et al. (Plos One, 2009), Thorsten et al. (NeuroReport, 2006, previously cited), Jeon et al. (Stem Cells, 2018, previously cited), and Shim et al. (WO 2015/119575 A2, 2015, previously cited).
In regards to claims 16, and 18-20, Fedele teaches a chemically defined serum-free medium cell medium for culturing dopaminergic midbrain precursors (Figure 1, p3; Results, p2; Supplement, p10).
Fedele teaches that the medium is supplemented with KO serum replacement (Supplement, p10), which while serum free, is known in the art not to be xenogeneic material-free (“xeno-free” as referred to in the art).
However, it is long-known in the art that midbrain dopaminergic precursors can be cultured in xeno-free conditions.
Specifically, Swistowski teaches that knockout serum replacement contains undefined xenogenic factors, which are a concern for clinical application (Introduction, p1). Switowski also teaches that midbrain dopaminergic precursors can be cultured in xeno-free conditions (Title, Abstract, p1; Fig. 4, p7) and recommends its use for therapeutic application (p10, Discussion, last paragraph). Therefore, a person of ordinary skill in the art would have been motivated to modify the composition of Fedele and specifically use xeno-free conditions because it would be most suitable for clinical application. Furthermore, because Swistowski explicitly teaches that midbrain dopaminergic precursors can be cultured in xeno-free media (and supplemented with at least FGF8 and SHH) (Title, Abstract, p1; Fig. 4, p7), a person of ordinary skill in the art could have adapted the composition of Fedele to xeno-free conditions with predictable results and a reasonable expectation of success.
Continuing, Fedele teaches that the medium comprises (thus, is supplemented with) FGF8, purmorphamine and Shh (both Hh signaling agonists), and CHIR99021 (a Wnt signaling agonist or GSK3 inhibitor) (Figure 1, p3). Fedele also teaches that these cells are useful for studying disease mechanisms, drug discovery, and eventually for cell replacement therapy (Abstract, p1). Fedele teaches that the medium is a chemically defined, serum-free medium (Results, p2).
Fedele is silent on whether the FGF8 is FGF8b specifically.
However, Thorsten teaches a medium for culturing dopaminergic precursors media comprising FGF8b and Shh (a Hh signaling agonist) (Abstract, p975). Thorsten teaches that this promotes cell proliferation and that withdrawal of these growth factors leads to differentiation into predominantly dopaminergic precursors (Abstract, p975). Therefore, a person of ordinary skill in the arts would be motivated to modify the method of Fedele and use FGF8b specifically, because it would be efficient for generating more dopaminergic precursors which could be used to study disease, drugs, or potential therapies. Furthermore, because Thorsten demonstrates that dopaminergic precursors can be expanded with FGF8b, and because Fedele and Thorsten are in the same technical field of culturing dopaminergic precursors, it could be done with predictable results and a reasonable expectation of success.
Fedele does not explicitly teach that the medium comprises a Wnt antagonist (or specifically Wnt-C59), however, Jeon teaches that WNT-C59 can be added to media (p212, Figure 6), and that this inhibits induction of posterior markers and abrogates suppression of anterior markers (p211, column 1, GLIS3-mediated posterior specification is WNT-dependent). In particular, Jeon teaches that treatment with WNT-C59 leads to an increase in the number of OTX2 positive cells (p211, column 1, GLIS3-mediated posterior specification is WNT-dependent), which is well known to be a marker characteristic of dopaminergic neural progenitor cells (as evidenced by Applicant’s specification, paragraph [00030]).
Therefore, a person of ordinary skill in the arts would be motivated to modify the method of Fedele and add Wnt-C59 to the media composition because it would be useful for avoiding expression of posterior neural markers, and promote expression of anterior markers such as OTX2 which is a marker for dopaminergic progenitor cells.
Furthermore, while WNT-C59 is a Wnt antagonist and CHIR99021 is a Wnt agonist, it was known in the art prior to the effective filing date that Wnt antagonists and agonists could be used in combination for the culturing of neuronal cells. For example, as taught by Shim cells can be contacted with both IWP4 (a Wnt antagonist) and CHIR99021 (p19, lines 3-9).
Therefore, because Jeon teaches that WNT-C59 supplementation promotes OTX2 expression, which is a known dopaminergic neural progenitor marker, because Shim teaches that Wnt antagonists and agonists can be used in combination, and because Fedele teaches a composition for culturing dopaminergic precursors, it could be done with predictable results and a reasonable expectation of success.
In regards to whether the composition is capable of promoting proliferation of dopaminergic neuron progenitor cells without losing their identity and without differentiation thereof, it is noted that the composition does not require these cells, but rather describes a property of the composition if uses as a culture medium.
It is therefore, an intended use of the composition (see MPEP 2111.02). A composition claim defines what the invention is, not what it does (which would be a method claim). To satisfy an intended use limitation which is limiting, a prior art structure which is capable of performing the intended use meets the claim. See, e.g., In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997).
In regards to the composition of Fedele, Fedele also teaches that cells cultured in the medium were passaged, reseeded, and expanded (Results, p2; Fig. 1, p3; Fig. 6, p8).
Furthermore, because Fedele explicitly refers to the cells as dopaminergic progenitor cells and describes differentiation of these cells in further steps (which requires a different medium), it suggests that these cells also retain DA NPC identity without differentiation.
Moreover, this is confirmed by Swistowski who also teaches that DA precursors can be cultured over extended times under xeno-free conditions and with at least SHH and FGF8, and that terminal differentiation requires a different medium (Fig. 4, p7).
Therefore, the composition of Fedele has the same property of promoting proliferation of dopaminergic neuron progenitor cells without losing their identity and without differentiation thereof, or is at least suitable for this purpose.
In regards to claim 17, in regards to a “serum-free supplement adapted for a neural cell culture”, it is noted that this phrase is not defined in the disclosure, and is also not specifically defined in the art. Therefore, giving the term is broadest reasonable interpretation, it has been interpreted as any serum-free supplement that is suitable for neural cell culture.
To this end, Fedele teaches that cells were supplemented with BMP4 inhibitor LDN-193189 (p9; Fig. 1), which is specific compound, not in serum, and therefore, is a “serum-free supplement adapted for a neural cell culture” as discussed above.
Therefore, the combined teachings of Fedele, Swistowski, Thorsten, Jeon, and Shim render the invention unpatentable as claimed.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Fedele et al. (Nature Scientific Reports, 2017, on IDS 04/21/2021, previously) in view Swistowski et al. (Plos One, 2009), Thorsten et al. (NeuroReport, 2006, previously cited), Jeon et al. (Stem Cells, 2018, previously cited), and Shim et al. (WO 2015/119575 A2, 2015, previously cited) as applied to claims 16 and 18 above, and further in view of Xi et al. (Stem Cells, 2012, on IDS 04/21/2021).
In regards to claim 21, Fedele teaches that concentration of CHIR99021 was 3 µM (In vitro expansion of floor plate midbrain progenitors and DA differentiation, supplementary p9), which while greater, a person of ordinary skill in the art could have arrived at a concentration of between 0.01 µM and 1 µM by routine optimization and the disclose does not point to a criticality in this concentration.
In regards to routine optimization, MPEP 2144.05(II)(A) states that differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
In the instant case, because Fedele teaches that different neural differentiation media can be mixed at different method steps (Results, p2), which would result in media with factors at different concentrations, and because Xi teaches that low concentrations of CHIR99021 (specifically, a narrow concentration of 0.2 to 0.6 µM, which overlaps with the claimed range (A specific CHIR99021 Concentration at a Particular Window is Necessary to Pattern the Midbrain Fate, p1657; Fig. 2, p1658), a person of ordinary skill in the art could have arrived at a concentration of between 0.01 µM and 1 µM by routine optimization with predictable results and a reasonable expectation of success.
Indeed, a person of ordinary skill in the art would have been specifically motivated to use a lower concentration (between 0.01 µM and 1 µM) because Xi teaches that concentrations within this range are most effective for generating midbrain cells (A specific CHIR99021 Concentration at a Particular Window is Necessary to Pattern the Midbrain Fate, p1657; Fig. 2, p1658). Furthermore, because Xi demonstrates that midbrain cells can be cultured in a range of concentrations that overlap with the claimed range, and because Fedele and Xi are in the same technical field of culturing midbrain cells, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Fedele, Swistowski, Thorsten, Jeon, Shim, and Xi render the invention unpatentable as claimed.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Fedele et al. (Nature Scientific Reports, 2017, on IDS 04/21/2021, previously) in view Swistowski et al. (Plos One, 2009), Thorsten et al. (NeuroReport, 2006, previously cited), Jeon et al. (Stem Cells, 2018, previously cited), Shim et al. (WO 2015/119575 A2, 2015, previously cited), and Xi et al. (Stem Cells, 2012, on IDS 04/21/2021), as applied to claims 16, 18, and 21 above, and further in view of Rostovskaya et al. (Development, 2019)
In regards to claim 22, Jeon teaches that the concentration of WNT-C59 was 100 nM (0.1 nM) (Figure 6, p212). While less than the range of 0.2 to 10 µM, it is nonetheless close. According to MPEP 2144.05(I), “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).”
Moreover, a person of ordinary skill in the arts could have arrived at a concentration range of 0.2 to 10 µM by routine optimization, and the disclosure does not point to a criticality in this range (see MPEP2144.05(II)(A), “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”). In the instant case because determining workable concentrations of reagents is a routine laboratory practice, and because as taught by Rostovskaya, it is known in the art that C-59 can be used to control Wnt signaling at a concentration of 1 µM (Capacitation, p10), which overlaps with the claimed range of 0.5 µM to 10 µM, a person of ordinary skill in the art could have arrived at this concentration by routine optimization, with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Fedele, Swistowski, Thorsten, Jeon, Shim, Xi, and Rostovskaya render the invention unpatentable as claimed.
Response to Arguments
In regards to the xeno-free media, Applicant argues that the KO media as taught by Fedele does contains numerous components of unknown composition (Remarks, p7). Continuing, Applicant argues that while Wang discloses that iPSCs can be cultured under xeno-free conditions and differentiated to general neural progenitor cells, Wang does not specifically teach or suggest differentiation into dopaminergic midbrain precursors (Remarks, p7). Applicant, argues that differentiation into this lineage is uniquely complex and requires precise modulation of signaling pathways as well as midbrain formulations tailored to midbrain specification not disclosed in Wang (Remarks, p7). In regards to Fedele, Applicant argues that Fedele focuses on differentiation of dopaminergic neurons and yet employs non-xeno-free KO Serum Replacement (Remarks, p7). Applicant argues that importantly, Fedele does not teach that KO Serum Replacement is dispensable or that equivalents could be obtained under xeno-free conditions (Remarks, p7). Continuing, Applicant argues that at the time of the invention, the art recognized that even minor changes in medium composition could drastically alter lineage outcomes and success in differentiating neural progenitor cells and therefore, did not establish a predictability or reasonable expectation of success for obtaining dopaminergic midbrain precursors (Remarks, p7).
Applicant’s arguments with respect to Wang have been considered but are moot because the new ground of rejection does not rely on Wang any teaching or matter specifically challenged in the argument.
However, in regards to Applicant’s arguments against Fedelel, Applicant’s arguments filed 02/11/2026 have been fully considered but are not found persuasive.
It is long-known in the art that midbrain dopaminergic precursors specifically can be cultured in xeno-free conditions.
As discussed above, while Fedele teaches that the medium is supplemented with KO serum replacement (Supplement, p10), which while serum free, is known in the art not to be xenogeneic material-free (“xeno-free” as referred to in the art), Swistowski teaches that knockout serum replacement contains undefined xenogenic factors, which are a concern for clinical application (Introduction, p1). Switowski also teaches that midbrain dopaminergic precursors can be cultured in xeno-free conditions (Title, Abstract, p1; Fig. 4, p7) and recommends its use for therapeutic application (p10, Discussion, last paragrpah).
Therefore, a person of ordinary skill in the art would have been motivated to modify the composition of Fedele and specifically use xeno-free conditions because it would be most suitable for clinical application. Furthermore, because Swistowski explicitly teaches that midbrain dopaminergic precursors can be cultured in xeno-free media (and supplemented with at least FGF8 and SHH) (Title, Abstract, p1; Fig. 4, p7), a person of ordinary skill in the art could have adapted the composition of Fedele to xeno-free conditions with predictable results and a reasonable expectation of success.
Therefore, despite Applicant’s arguments, serum knockout serum replacement is in fact dispensable.
Applicant argues that a critical objective of the present invention is to promote cellular proliferation while preserving dopaminergic identity, that the prior art’s disclosure of one or two individual components, in isolation does not teach or suggest the claims approach, nor provide guidance on how to achieve proliferation without loss of dopaminergic characteristics (Remarks, p7-8).
In regards to Fedele, Applicant argues that Fedele expressly states that SHH and FGF8 did not increase midbrain floor plate (mFPP) (citing Fig 1), which Applicant argues that demonstrates that culturing cells in a “floor plate expansion medium” results in an increase in floor plate cells but does not demonstrate a corresponding expansion of dopaminergic progenitors (Remarks, p8). Applicant also argues that Fig. 4B of Fedel shows non-specific LMX1A staining which indicates the absence of bona fide dopaminergic progenitor identity (Remarks, p8).
In regards to Thorsten, Applicant argues that although Thorsten refers to proliferation of neuronal precursor cells, the proliferation is explicitly conducted under conditions intended to promote dopaminergic differentiation rather than maintenance in an undifferentiated progenitor state (Remarks, p9). Applicant argues that this is underscored by Thorsten’s understanding of how EGF, FF8b, SHH, and L-ascorbic acid act to promote differentiation (Remarks, p9).
Applicant’s arguments filed 02/11/2026 have been fully considered but are not found persuasive.
All of the claimed components and conditions where known in the art before the effecting filing date. As discussed above, Fedele teaches a chemically defined serum-free medium cell medium for culturing dopaminergic midbrain precursors (Figure 1, p3; Results, p2; Supplement, p10) comprising FGF8, purmorphamine and Shh (both Hh signaling agonists), and CHIR99021 (a Wnt signaling agonist or GSK3 inhibitor) (Figure 1, p3).
Thus, the difference is that the composition of Fedele is not xeno-free, does not comprise WNT-C59, and Fedele is silent as to the specific FGF8.
However, as discussed above, it is long-known in the art that midbrain dopaminergic precursors can be cultured in xeno-free conditions.
Specifically, as above, Switowski teaches that midbrain dopaminergic precursors can be cultured in xeno-free conditions (Title, Abstract, p1; Fig. 4, p7) and recommends its use for therapeutic application (p10, Discussion, last paragrpah).
Therefore, a person of ordinary skill in the art would have been motivated to modify the composition of Fedele and specifically use xeno-free conditions because it would be most suitable for clinical application. Furthermore, because Swistowski explicitly teaches that midbrain dopaminergic precursors can be cultured in xeno-free media (and supplemented with at least FGF8 and SHH) (Title, Abstract, p1; Fig. 4, p7), a person of ordinary skill in the art could have adapted the composition of Fedele to xeno-free conditions with predictable results and a reasonable expectation of success.
In regards to WNT-C59, as above, Jeon teaches that WNT-C59 can be added to media (p212, Figure 6), and that this inhibits induction of posterior markers and abrogates suppression of anterior markers (p211, column 1, GLIS3-mediated posterior specification is WNT-dependent). In particular, Jeon teaches that treatment with WNT-C59 leads to an increase in the number of OTX2 positive cells (p211, column 1, GLIS3-mediated posterior specification is WNT-dependent), which is well known to be a marker characteristic of dopaminergic neural progenitor cells (as evidenced by Applicant’s specification, paragraph [00030]).
Therefore, a person of ordinary skill in the arts would be motivated to modify the method of Fedele and add Wnt-C59 to the media composition because it would be useful for avoiding expression of posterior neural markers, and promote expression of anterior markers such as OTX2 which is a marker for dopaminergic progenitor cells.
Furthermore, while WNT-C59 is a Wnt antagonist and CHIR99021 is a Wnt agonist, it was known in the art prior to the effective filing date that Wnt antagonists and agonists could be used in combination for the culturing of neuronal cells. For example, as taught by Shim cells can be contacted with both IWP4 (a Wnt antagonist) and CHIR99021 (p19, lines 3-9).
Therefore, because Jeon teaches that WNT-C59 supplementation promotes OTX2 expression, which is a known dopaminergic neural progenitor marker, because Shim teaches that Wnt antagonists and agonists can be used in combination, and because Fedele teaches a composition for culturing dopaminergic precursors, it could be done with predictable results and a reasonable expectation of success.
In regards to FGF8b specifically, as above, Thorsten teaches a medium for culturing dopaminergic precursors media comprising FGF8b and Shh (a Hh signaling agonist) (Abstract, p975). Thorsten teaches that this promotes cell proliferation and that withdrawal of these growth factors leads to differentiation into predominantly dopaminergic precursors (Abstract, p975). Therefore, a person of ordinary skill in the arts would be motivated to modify the method of Fedele and use FGF8b specifically, because it would be efficient for generating more dopaminergic precursors which could be used to study disease, drugs, or potential therapies. Furthermore, because Thorsten demonstrates that dopaminergic precursors can be expanded with FGF8b, and because Fedele and Thorsten are in the same technical field of culturing dopaminergic precursors, it could be done with predictable results and a reasonable expectation of success.
In regards to whether the composition is capable of promoting proliferation of dopaminergic neuron progenitor cells without losing their identity and without differentiation thereof, it is noted that the composition does not require these cells, but rather describes a property of the composition if uses as a culture medium.
It is therefore, an intended use of the composition (see MPEP 2111.02). A composition claim defines what the invention is, not what it does (which would be a method claim). To satisfy an intended use limitation which is limiting, a prior art structure which is capable of performing the intended use meets the claim. See, e.g., In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997).
In regards to the composition of Fedele, Fedele also teaches that cells cultured in the medium were passaged, reseeded, and expanded (Results, p2; Fig. 1, p3; Fig. 6, p8).
Furthermore, because Fedele explicitly refers to the cells as dopaminergic progenitor cells and describes differentiation of these cells in further steps (which requires a different medium), it suggests that these cells also retain DA NPC identity without differentiation.
Moreover, this is confirmed by Swistowski who also teaches that DA precursors can be cultured over extended times under xeno-free conditions and with at least SHH and FGF8, and that terminal differentiation requires a different medium (Fig. 4, p7).
Therefore, the composition of Fedele has the same property of promoting proliferation of dopaminergic neuron progenitor cells without losing their identity and without differentiation thereof, or is at least suitable for this purpose.
In regards to Applicant’s augment that Fedele expressly states that SHH and FGF8 did not increase midbrain floor plate (mFPP) (citing Fig 1), this is not germane to the suitability of medium of Fedele to perform the intended use because at least, the use of the composition is not drawn to expanding midbrain floor plate cells. And again, as above, Fedele explicitly teaches that dopaminergic progenitor cells expand.
In regards to Applicant’s argument that non-specific LMX1A staining which Applicant indicates the absence of bona fide dopaminergic progenitor identity, Fedele in multiple instances explicitly describes the existence of expanded dopaminergic progenitor cells (Figs. 1 and 6).
In regards to Thorsten, and as noted by applicant, FGF8b is specifically used during the “proliferation stage” (Discussion, p978) which “induces cell proliferation” (Abstract, p975), and therefore, is suitable for proliferation of cells, regardless of whether they are later differentiated.
Furthermore, in regards to other reagents (EGF etc.), Thorsten explicitly states that it is the withdrawal of these regents (which includes FGF8b, see Abstract, p975) that results in differentiation.
Applicant argues that Jeon’s teaching that WNT-C59 supplementation is flawed because OTX2 expression alone is not indicative of midbrain dopaminergic progenitors, as OTX2 is also a marker of forebrain neural progenitors (Remarks, p9).
Applicant’s arguments filed 02/11/2026 have been fully considered but are not found persuasive.
As noted by Applicant, OTX2 is a midbrain dopaminergic progenitors, and therefore, a person of ordinary skill in the art would have been motivated to target expression of this marker in a composition for culturing midbrain dopaminergic progenitors (such as taught by Fedele).
Whether it may also be a marker for forebrain neural progenitors is not germane to the composition of Fedele, because the composition of Fedele explicitly produces a midbrain dopaminergic progenitors, not forebrain neural progenitors, and the marker is still indicative of midbrain dopaminergic progenitors.
Applicant argues that the obviousness reference is based on 5 references and that this indicates hindsight reasoning (Remarks, p10).
Applicant’s arguments filed 02/11/2026 have been fully considered but are not found persuasive.
In response to applicant's argument that the examiner has combined an excessive number of references, reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention. See In re Gorman, 933 F.2d 982, 18 USPQ2d 1885 (Fed. Cir. 1991).
In regards to hindsight reasoning, In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant argues that no combination of the cited prior art teaches a composition of a chemically defined, serum-free, and xenogeneic material-free cell culture media supplemented with factors that include FGF8, an agonist of Hh signaling, a small molecule against canonical Wnt signaling, and WNT-C59, wherein the composition is capable of promoting proliferation, etc. as in claim 16 (Remarks, p10-11).
Specifically, Applicant argues that there is no motivation to combine the references to form the claimed invention, and that a person of ordinary skill in the art would have understood that, as a consequence of the differences between the compositions of Fedele, etc., the former compositions do not teach or suggest that the compositions of the instant application would be operative for dopaminergic cell expansion (Remarks, p10-11).
Applicant’s arguments filed 02/11/2026 have been fully considered but are not found persuasive.
Specific motivation for modifying the composition of Fedele is discussed in regards to the cited art as discussed above.
In regards to the claimed invention, as discussed above, teaches a chemically defined serum-free medium cell medium for culturing dopaminergic midbrain precursors (Figure 1, p3; Results, p2; Supplement, p10).
Fedele teaches that the medium is supplemented with KO serum replacement (Supplement, p10), which while serum free, is known in the art not to be xenogeneic material-free (“xeno-free” as referred to in the art).
However, it is long-known in the art that midbrain dopaminergic precursors can be cultured in xeno-free conditions.
Specifically, Swistowski teaches that knockout serum replacement contains undefined xeneogenic factors, which are a concern for clinical application (Introduction, p1). Switowski also teaches that midbrain dopaminergic precursors can be cultured in xeno-free conditions (Title, Abstract, p1; Fig. 4, p7) and recommends its use for therapeutic application (p10, Discussion, last paragraph). Therefore, a person of ordinary skill in the art would have been motivated to modify the composition of Fedele and specifically use xeno-free conditions because it would be most suitable for clinical application. Furthermore, because Swistowski explicitly teaches that midbrain dopaminergic precursors can be cultured in xeno-free media (and supplemented with at least FGF8 and SHH) (Title, Abstract, p1; Fig. 4, p7), a person of ordinary skill in the art could have adapted the composition of Fedele to xeno-free conditions with predictable results and a reasonable expectation of success.
Continuing, Fedele teaches that the medium comprises (thus, is supplemented with) FGF8, purmorphamine and Shh (both Hh signaling agonists), and CHIR99021 (a Wnt signaling agonist or GSK3 inhibitor) (Figure 1, p3). Fedele also teaches that these cells are useful for studying disease mechanisms, drug discovery, and eventually for cell replacement therapy (Abstract, p1). Fedele teaches that the medium is a chemically defined, serum-free medium (Results, p2).
Fedele is silent on whether the FGF8 is FGF8b specifically.
However, Thorsten teaches a medium for culturing dopaminergic precursors media comprising FGF8b and Shh (a Hh signaling agonist) (Abstract, p975). Thorsten teaches that this promotes cell proliferation and that withdrawal of these growth factors leads to differentiation into predominantly dopaminergic precursors (Abstract, p975). Therefore, a person of ordinary skill in the arts would be motivated to modify the method of Fedele and use FGF8b specifically, because it would be efficient for generating more dopaminergic precursors which could be used to study disease, drugs, or potential therapies. Furthermore, because Thorsten demonstrates that dopaminergic precursors can be expanded with FGF8b, and because Fedele and Thorsten are in the same technical field of culturing dopaminergic precursors, it could be done with predictable results and a reasonable expectation of success.
Fedele does not explicitly teach that the medium comprises a Wnt antagonist (or specifically Wnt-C59), however, Jeon teaches that WNT-C59 can be added to media (p212, Figure 6), and that this inhibits induction of posterior markers and abrogates suppression of anterior markers (p211, column 1, GLIS3-mediated posterior specification is WNT-dependent). In particular, Jeon teaches that treatment with WNT-C59 leads to an increase in the number of OTX2 positive cells (p211, column 1, GLIS3-mediated posterior specification is WNT-dependent), which is well known to be a marker characteristic of dopaminergic neural progenitor cells (as evidenced by Applicant’s specification, paragraph [00030]).
Therefore, a person of ordinary skill in the arts would be motivated to modify the method of Fedele and add Wnt-C59 to the media composition because it would be useful for avoiding expression of posterior neural markers, and promote expression of anterior markers such as OTX2 which is a marker for dopaminergic progenitor cells.
Furthermore, while WNT-C59 is a Wnt antagonist and CHIR99021 is a Wnt agonist, it was known in the art prior to the effective filing date that Wnt antagonists and agonists could be used in combination for the culturing of neuronal cells. For example, as taught by Shim cells can be contacted with both IWP4 (a Wnt antagonist) and CHIR99021 (p19, lines 3-9).
Therefore, because Jeon teaches that WNT-C59 supplementation promotes OTX2 expression, which is a known dopaminergic neural progenitor marker, because Shim teaches that Wnt antagonists and agonists can be used in combination, and because Fedele teaches a composition for culturing dopaminergic precursors, it could be done with predictable results and a reasonable expectation of success.
In regards to whether the composition is capable of promoting proliferation of dopaminergic neuron progenitor cells without losing their identity and without differentiation thereof, it is noted that the composition does not require these cells, but rather describes a property of the composition if uses as a culture medium.
It is therefore, an intended use of the composition (see MPEP 2111.02). A composition claim defines what the invention is, not what it does (which would be a method claim). To satisfy an intended use limitation which is limiting, a prior art structure which is capable of performing the intended use meets the claim. See, e.g., In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997).
In regards to the composition of Fedele, Fedele also teaches that cells cultured in the medium were passaged, reseeded, and expanded (Results, p2; Fig. 1, p3; Fig. 6, p8).
Furthermore, because Fedele explicitly refers to the cells as dopaminergic progenitor cells and describes differentiation of these cells in further steps (which requires a different medium), it suggests that these cells also retain DA NPC identity without differentiation.
Moreover, this is confirmed by Swistowski who also teaches that DA precursors can be cultured over extended times under xeno-free conditions and with at least SHH and FGF8, and that terminal differentiation requires a different medium (Fig. 4, p7).
Therefore, the composition of Fedele has the same property of promoting proliferation of dopaminergic neuron progenitor cells without losing their identity and without differentiation thereof, or is at least suitable for this purpose.
Therefore, all of the claimed limitations were disclosed in the cited prior art, there was predictable motivation to modify the composition of Fedele, Fedele is not deficient, and the claims are prima facie obvious.
Conclusion
No claims are allowed.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
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