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 .
DETAILED ACTION
Election/Restriction
Applicant’s election, without traverse, of Group I, claims 1-15, drawn to a method for generating a three-dimensional neuromuscular organoid in vitro, in the reply filed on 11/06/2025 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Claims 16-21 and 24-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable linking claim.
Claim Status
Claims 1-21 and 24-25 are pending.
Claims 16-21 and 24-25 are withdrawn.
Claims 1-15 are considered on the merits.
Priority
This application is a 371 of PCT/EP2021/069325 (filed on 07/12/2021), which claims benefit from Application 63/050,736 (filed on 07/10/2020). The priority claim has been granted with the earliest benefit date of 07/10/2020 from Application 63/050,736.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01/10/2023, 10/27/2023, 04/18/2025 and 04/28/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. The corresponding signed and initialed PTO forms 1449 have been mailed with this action.
Specification Objections
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (e.g., page 34, line 26 and page 38, line 23). Applicant is required to amend or delete the embedded hyperlink and/or other form of browser-executable code. For example, “www” can be replaced with “world wide web” as the URL code. See MPEP § 608.01.
Claim Objections
Claims 1, 6, 9 and 14 are objected to because of the following informalities:
Claim 1 (b) line 2, claim 6, lines 3 and 4, and claim 14, line 4, all recite the phrase “after cultivation start”. Since the term “cultivation” is primarily used as a singular, it is recommended to change the phrase to “after cultivation starts”.
Claim 9 recites the phrase “first cultivation medium” in line 1. Since base claim 8 recites a first cultivation medium, it is recommended to change the phrase to “the first cultivation medium”.
Appropriate correction is required.
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 1-15 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 1 (d) and claim 2 recite the limitation “the non-supplemented serum-free cell culture medium”. There is insufficient antecedent basis for this limitation in the claims because claim 1 (a), (b) and (c) all recite “a non-supplemented serum-free cell culture medium”, so it is not clear which medium this limitation in claim 1 (d) or claim 2 is referring to. For the sake of compact prosecution, the limitation is being examined as referring to any one of the medium in claim 1 (a), (b) or (c). Claims 3-15 are rejected as being directly or indirectly dependent from claim 1 but not resolving the ambiguity.
Claim 3 recites the limitation “the activator of a growth factor signaling pathway”. There is insufficient antecedent basis for this limitation in the claim because claim 1 (a) and (b) both recite “an activator of a growth factor signaling pathway”, so it is not clear which activator this limitation in claim 3 is referring to. The limitation is being examined as referring to any one of the activator in claim 1 (a) or (b).
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 1-15 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Under the written description guidelines (see MPEP 2163) the Examiner is directed to determine whether one skilled in the art would recognize that the Applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination.
To satisfy the written description requirement, a patent 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. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement." Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Accordingly, 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.
SCOPE OF THE INVENTION
Independent claim 1 encompasses a genus of method for generating a 3D neuromuscular organoid in vitro comprising cultivating disease-specific neuromesodermal progenitor cells (NMPs) in a first differentiation medium and a second differentiation medium comprising a serum-free medium supplemented with at least one of a genus of activators of a genus of growth factor signaling pathways and a genus of activators of an insulin signaling pathway.
Since the specification does not provide a definition of an activator or a growth factor, the scope of claim 1 encompasses a genus of methods comprising cultivating NMPs in any serum-free medium supplemented with any types of activators (e.g., a protein ligand, a small molecule ligand, an mRNA encoding a ligand, a protein inhibitor of an inhibitory mediator, a small molecule inhibitor of an inhibitory mediator, an RNAi targeting an inhibitory mediator) of a genus of growth factor signaling pathways (e.g., any factor that has any growth-supporting function on any type of cells under any context), in any combination, at any concentration, for any duration, on any culture container, under any culture condition, so as to obtain a 3D neuromuscular organoid.
However, the specification only discloses one method comprising cultivating NMPs on an ultra-low binding 96-well plate in a neurobasal (NB) medium supplemented with 50uM ROCK inhibitor, 10ng/ml bFGF and 2ng/ml IGF1 and 2ng/ml HGF for two days (Day 0 – Day 2), partially changing media with a second medium comprising NB medium supplemented with 2ng/ml IGF1 and 2ng/ml HGF and cultivating for two days (Day 2 – Day 4), changing media to NB medium without addition of growth factors and maintaining for 6 days (Day 4 – Day 10, with possible media changes), and transferring to bigger dishes with the same medium without addition of growth factors for continuous cultivation to about Day 50 or more, and during the whole period organoids are maintained on an orbital shaker with rotation (see specification, page 32, para “Generation of neuromuscular organoids in 3D”).
Dependent claims 2-7 encompass limitations regarding one of the aspects encompassed by independent claim 1, such as the serum-free medium, the first differentiation medium, the second differentiation medium, medium change schedule, or agitation. However, the specification only discloses a single species of method comprising a specific combination of the above aspects.
Dependent claims 8-15 encompass a genus of second cell culture for obtaining NMPs by cultivating pluripotent stem cells (PSCs) in a first cultivation medium comprising any serum-free medium supplemented with a genus of activators of β-catenin signaling pathway and a genus of activators of a genus of growth factor signaling pathways, and in a second cultivation medium including a serum-free medium supplemented with a genus of activators of β-catenin signaling pathway and a genus of activators of a genus of growth factor signaling pathways, in any combination, at any concentration, for any duration. However, the specification only discloses a single species of the second cell culture comprising cultivating PSCs in a first cultivation medium comprising a specific serum-free medium (NB medium) supplemented with a specific set of activators and concentrations (10uM ROCK inhibitor, 3uM CHIR99021 and 40ng/ml bFGF) for one day, and cultivating in a second cultivation medium comprising a NB medium supplemented with a specific set of activators (3uM CHIR99021 and 40ng/ml bFGF) for one day, to obtain NMPs (see specification, p. 31-32, para “In vitro generation of NMPs from human pluripotent stem cells”).
ACTUAL REDUCTION TO PRACTICE
As stated supra, the claims encompass a genus of methods for generating neuromuscular organoid and a genus of methods for obtaining NMPs. However, the specification only discloses a single species of the method, respectively.
Accordingly, Applicant did not demonstrate a reduction to practice a genus of methods for generating neuromuscular organoid or a genus of methods for obtaining NMPs, nor did Applicant adequately set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention that are sufficiently detailed to show that Applicant was in possession of the claimed genus of methods.
DISCLOSURE OF STRUCTURE
The Applicant has provided no other working examples besides the single example of the respective method as discussed above. Although generating a 3D neuromuscular organoid is known in the field, the prior art is silent on a method of cultivating NMPs under the broad genus of conditions encompassed by the claims, nor indicate a relationship between the structure of the claimed conditions and the ability to generate a 3D neuromuscular organoid.
SUFFICIENT RELEVANT IDENTIFYING CHARACTERISTICS
As mentioned in above, generating a 3D neuromuscular organoid is known in the field, and the skilled artisan could co-culture neurons and muscular cells to generate a neuromuscular organoid.
The breath of the claims encompasses a genus of methods comprising cultivating NMPs in any serum-free medium supplemented with any types of activators of a genus of growth factor signaling pathways, in any combination, at any concentration, for any duration, on any culture container, under any culture condition, so as to obtain a 3D neuromuscular organoid, yet the present specification provides no guidance nor description on how a neuromuscular organoid would be generated by cultivating NMPs under such a broad genus of conditions, therefore the skilled artisan would not know what rational approach to take to use the claimed method to predictably generate a neuromuscular organoid. Therefore, it is incumbent on the applicant to provide this nexus between structure and function, in order to be given credit for possession of the claimed genus of method.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method of making the claimed invention is not well established. Although the method for cultivating NMPs under a specific condition was known in the state of the art, one of skill in the art would neither expect nor predict the method may generate a neuromuscular organoid by cultivating NMPs under such a broad genus of conditions.
With respect to cultivating NMPs under different conditions, prior art Gouti et al., (PLoS Biol. 2014; 12(8): e1001937, p. 1-15. Cited in IDS 01/10/2023) teaches that cultivating NMPs (from Day 3 in Figures 1-3 and 5-6) in media supplemented with activators of different growth factor signaling pathways results in differentiating the NMPs into different terminal tissue types. For example, Figure 2 shows cultivating NMPs from D3 in media with RA/SAG (activators of hedgehog signaling pathway) generates “Np” (posterior spinal cord), while cultivating with CHIR (activator of wnt signaling pathway) generates “Meso” (mesodermal tissue). Consequently, there is ample reason to conclude that there would be a high degree of unpredictability in generating a neuromuscular organoid by cultivating NMPs with any activators of a genus of growth factor signaling pathways. Thus, the method of generating a neuromuscular organoid by cultivating NMPs is highly unpredictable, and is not well established.
Applicant has claimed a genus of methods for generating a neuromuscular organoid by cultivating NMPs, yet the specification has only disclosed a single species of method, has not set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention that are sufficiently detailed to show that Applicant was in possession of the claimed genus of method. Furthermore, the state of the art indicated that a method for generating a neuromuscular organoid by cultivating NMPs is not well established and would require undue experimentation, and one of skill in the art would neither expect nor predict the claimed outcome of generating a neuromuscular organoid according to the claimed genus of method of cultivating NMPs encompassed by the scope of the claims.
CONCLUSION
In summary, the Examiner concludes that there is insufficient written description of the instantly claimed genus of method of generating a neuromuscular organoid by cultivating NMPs. Specifically, there is limited description of the method of generating a neuromuscular organoid by cultivating NMPs, and limited description of the structure-function relationship between the claimed genus of methods and their ability to generate a neuromuscular organoid, and the Examiner further concludes a skilled artisan would find the specification inadequately describes the claimed genus of method for generating a neuromuscular organoid by cultivating NMPs.
Therefore, the specification fails to provide sufficient written description to inform a skilled artisan that inventors were in possession of the entire scope of the claimed invention.
(Scope of Enablement)
Claims 1-15 are 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 generating a 3D neuromuscular organoid in vitro comprising cultivating NMPs in a non-supplemented serum-free medium or a neurobasal (NB) medium supplemented with a ROCK inhibitor, bFGF, IGF1 and HGF for 1 to 4 days, replacing the medium by a second medium comprising a non-supplemented serum-free medium or an NB medium supplemented with IGF1 and HGF and cultivating for 1 to 4 days, and replacing the medium by an NB medium without addition of growth factors to obtain a 3D neuromuscular organoid (see e.g., specification, page 32, para “Generation of neuromuscular organoids in 3D”), does not reasonably provide enablement for a method comprising cultivating NMPs in any serum-free medium supplemented with any types of activators of a genus of growth factor signaling pathways, in any combination, at any concentration, for any duration, on any culture container, under any culture condition, to obtain a 3D neuromuscular organoid. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
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.
The office has analyzed the specification in direct accordance to the factors outlined in In re Wands. MPEP 2164.04 states: "[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection." These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform "undue experimentation" to make and/or use the invention and therefore, Applicant's claims are not enabled commensurate with the scope of the invention.
SCOPE OF THE INVENTION
The breadth of the claims encompasses a genus of method comprising cultivating NMPs in any serum-free medium supplemented with any types of activators of a genus of growth factor signaling pathways, in any combination, at any concentration, for any duration, on any culture container, under any culture condition, to obtain a 3D neuromuscular organoid.
As discussed supra, the specification fails to describe the genus of methods. The specification only discloses and provides guidance for a single species of method for generating neuromuscular organoid by cultivating NMPs in a neurobasal (NB) medium supplemented with a ROCK inhibitor, bFGF, IGF1 and HGF for 1 to 4 days, replacing the medium by a second medium comprising an NB medium supplemented with IGF1 and HGF and cultivating for 1 to 4 days, and replacing the medium by an NB medium without addition of growth factors (see e.g., specification, page 32, para “Generation of neuromuscular organoids in 3D”).
Independent claim 1 encompasses a genus of method for generating a 3D neuromuscular organoid in vitro comprising cultivating disease-specific neuromesodermal progenitor cells (NMPs) in a first differentiation medium and a second differentiation medium comprising a serum-free medium supplemented with at least one of a genus of activators of a genus of growth factor signaling pathways and a genus of activators of an insulin signaling pathway. However, the specification only discloses a single species of method comprising cultivating NMPs in a specific serum-free medium supplemented with a specific set of activators, at a specific concentration, for a specific duration, on a specific culture container, under a specific culture condition (with agitation), so as to obtain a 3D neuromuscular organoid.
Dependent claims 2-7 encompass limitations regarding one of the aspects encompassed by independent claim 1, such as the serum-free medium, the first differentiation medium, the second differentiation medium, medium change schedule, or agitation. However, the specification only discloses a single species of method comprising a specific combination of the above aspects.
Dependent claims 8-15 encompass a genus of second cell culture for obtaining NMPs by cultivating pluripotent stem cells (PSCs) in a first cultivation medium comprising any serum-free medium supplemented with a genus of activators of β-catenin signaling pathway and a genus of activators of a genus of growth factor signaling pathways, and in a second cultivation medium including a serum-free medium supplemented with a genus of activators of β-catenin signaling pathway and a genus of activators of a genus of growth factor signaling pathways, in any combination, at any concentration, for any duration. However, the specification only discloses a single species of the second cell culture comprising cultivating PSCs in a first cultivation medium comprising a specific serum-free NB medium supplemented with a specific set of activators at a specific concentration (10uM ROCK inhibitor, 3uM CHIR99021 and 40ng/ml bFGF) for one day, and cultivating in a second cultivation medium comprising a NB medium supplemented with a specific set of activators at a specific concentration (3uM CHIR99021 and 40ng/ml bFGF) for one day, to obtain NMPs (see specification, p. 31-32, para “In vitro generation of NMPs from human pluripotent stem cells”).
ACTUAL REDUCTION TO PRACTICE
As stated supra, the claims encompass a genus of methods for generating neuromuscular organoid and a genus of methods for obtaining NMPs. However, the specification only discloses a single species of the method, respectively.
The specification does not provide guidance for or a working example for a genus of method. The absence of working examples directed to a genus of method necessitates further experimentation. Therefore, the specification does not provide sufficient guidance on how to use the claimed genus of methods for generating neuromuscular organoid by cultivating NMPs. Accordingly, Applicant did not demonstrate a reduction to practice a genus of methods for generating neuromuscular organoid or a genus of methods for obtaining NMPs.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method of making the claimed invention is not well established. Although the method for cultivating NMPs under a specific condition was known in the state of the art, one of skill in the art would neither expect nor predict the method may generate a neuromuscular organoid by cultivating NMPs under such a broad genus of conditions.
Regarding cultivating NMPs under different conditions, prior art Gouti et al., (PLoS Biol. 2014; 12(8): e1001937, p. 1-15. Cited in IDS 01/10/2023) teaches that cultivating NMPs (from Day 3 in Figures 1-3 and 5-6) in media supplemented with activators of various growth factor signaling pathways results in differentiating the NMPs into different terminal tissue types. For example, Figure 2 shows cultivating NMPs from D3 in media with RA/SAG (activators of hedgehog signaling pathway) generates “Np” (posterior spinal cord), while cultivating with CHIR (activator of wnt signaling pathway) generates “Meso” (mesodermal tissue). Consequently, there is ample reason to conclude that there would be a high degree of unpredictability in generating a neuromuscular organoid by cultivating NMPs with any activators of a genus of growth factor signaling pathways. Thus, the method of generating a neuromuscular organoid by cultivating NMPs is highly unpredictable, and is not well established.
Since the prior art did not provide guidance for the genus of method, it is incumbent upon the instant specification to do so. Applicant has claimed a genus of methods for generating a neuromuscular organoid by cultivating NMPs, yet the specification has only disclosed a single species of method, has not set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention. Furthermore, the state of the art indicated that a method for generating a neuromuscular organoid by cultivating NMPs is not well established and would require undue experimentation, and one of skill in the art would neither expect nor predict the claimed outcome of generating a neuromuscular organoid according to the claimed genus of method of cultivating NMPs encompassed by the scope of the claims.
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, first paragraph 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 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 use the instant broadly claimed invention.
CONCLUSION
Therefore, since the art teaches that the method for generating neuromuscular organoid by cultivating NMPs is prone to influence by multiple factors, and is highly unpredictable, and the specification does not provide ample guidance with respect to a genus of method, one would be burdened with undue experimentation to use the claimed invention for generating neuromuscular organoid by cultivating NMPs under a genus of conditions encompassed by the invention.
In conclusion, given the breadth of the claims and the limited scope of the specification, an undue quantity of experimentation is required to use the invention beyond the scope of a method for generating a 3D neuromuscular organoid in vitro comprising cultivating NMPs in a non-supplemented serum-free medium or a neurobasal (NB) medium supplemented with a ROCK inhibitor, bFGF, IGF1 and HGF for 1 to 4 days, replacing the medium by a second medium comprising a non-supplemented serum-free medium or an NB medium supplemented with IGF1 and HGF and cultivating for 1 to 4 days, and replacing the medium by an NB medium without addition of growth factors to obtain a 3D neuromuscular organoid.
Examiner’s comment
Based on the limited scope of a method for generating a 3D neuromuscular organoid in vitro comprising cultivating NMPs in a non-supplemented serum-free medium or a neurobasal (NB) medium supplemented with a ROCK inhibitor, bFGF, IGF1 and HGF for 1 to 4 days, replacing the medium by a second medium comprising a non-supplemented serum-free medium or an NB medium supplemented with IGF1 and HGF and cultivating for 1 to 4 days, and replacing the medium by an NB medium without addition of growth factors to obtain a 3D neuromuscular organoid, enabled by Applicant’s specification and prior art, the prior art Martins and Gouti have been applied to make obvious this limited scope of method.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Rejections over Martins
Claims 1-15 are rejected under 35 U.S.C. 103 as being unpatentable over Martins et al., (Cell Stem Cell. 2020, 26, 172-186. Cited in IDS 01/10/2023).
Martins et al appear to be Applicant' s own work. Applicant may rely on the exception under 35 U.S.C. 102(b)(1)(A) to overcome this rejection using 35 U.S.C. 102(a)(1) art by a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application, and is therefore not prior art under 35 U.S.C. 102(a)(1). Alternatively, applicant may rely on the exception under 35 U.S.C. 102(b)(1)(B) by providing evidence of a prior public disclosure via an affidavit or declaration under 37 CFR 1.130(b).
With respect to claim 1, Martins teaches a method for generating a three-dimensional neuromuscular organoid in vitro (abstract).
Regarding claim 1a, Martins teaches that “neuromesodermal progenitors generated from human PSCs were dissociated using accutase to generate a single cell suspension. On day 0 of organoid formation, NMP cells (4,500 – 9,000 / well depending on the cell line) were plated on an ultra-low binding 96-well plate (Corning) in NB medium with 50uM Rho-associated protein kinase ROCK inhibitor (Tocris Bioscience), 10ng/ml bFGF and 2ng/ml IGF1 and 2ng/ml HGF (Peprotech) (Supplemental page e3, para 5)”. Martins teaches the number of NMP cells co-expressing the neural progenitor marker (SOX2) and the nascent mesodermal marker (T/BRA) is 75% ± 3.2 (see Supplemental Fig S1E and legend) and teaches TBX6 is highly expressed at Day 3 hPSC culture (see Suppl Fig S1C, equivalent to Day 0 NMPs in Fig 1A in which hPSC culture starts from Day -3). Thus, Martins teaches claim 1 a) providing a first cell culture comprising NMP cells, wherein 30% to 90% of NMP cells co-express BRA/SOX2 and likely 10% to 70% of NMP cells co-express TBX6, and cultivating the NMP cells in a first differentiation medium that is ii) a serum-free cell culture medium supplemented with at least one of a ROCK inhibitor, an activator of a growth factor signaling pathway, and an activator of an insulin signaling pathway.
However, Martins uses wildtype human PSCs or iPSCs in generating NMP cells, but does not use disease-specific iPSCs to generate disease-specific NMP cells.
Nevertheless, Martins clearly contemplates testing the neuromuscular organoids (NMOs) as a disease model, such as Martins teaches that “these findings recapitulated key aspects of the disease pathology, suggesting that NMOs reliably model such disorders, which will be useful for future studies” (p. 180, left col, end of para 2), and suggests that “NMOs from iPSC lines of patients with neuromuscular disorders could be used in the future to generate a completely patient-derived NMJ model in 3D. This would provide a platform to assess the effectiveness of different pharmacological agents in stabilizing the NMJ and promoting MN survival. It would also provide unprecedented access to the early stages of the diseases that precede clinical diagnosis” (p. 182, right col, para 1).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for generating NMOs in vitro by cultivating wildtype PSC-derived NMPs disclosed by Martins, by substituting with disease-specific PSC-derived NMPs as suggested by Martins with a reasonable expectation of success. Since Martins aims to use NMPs to generate a disease model and suggests patient-derived NMOs would provide a platform to assess the effectiveness of pharmacological agents and provide access to the early stages of the diseases that precede clinical diagnosis (p. 182, right col, para 1), one of ordinary skill in the art would have had a reason to substitute with disease-specific iPSC-derived NMPs to generate patient-derived NMOs in order to assess therapeutic effectiveness of agents and study the early stages of the diseases.
Regarding claim 1b, Martins teaches that at “day 2, 50ul of the medium was removed and 100ul of NB medium supplemented with 2ng/ml IGF1 and HGF was added (Supplemental page e3, para 5),” corresponding to the claim limitations b) replacing the first differentiation medium by a second differentiation medium within 1 to 4 days after cultivation starts, wherein the second differentiation medium is ii) a serum-free cell culture medium supplemented with at least one of an activator of a growth factor signaling pathway, and an activator of an insulin signaling pathway.
Regarding claim 1c, Martins teaches that “after day 4 the organoids were maintained in NB medium without the addition of growth factors (Supplemental page e3, para 6),” corresponding to the claim limitations c) replacing the second differentiation medium by a non-supplemented serum-free cell culture medium within 1 to 4 days after replacing the first differentiation medium by the second differentiation medium.
Regarding claim 1d, Martins teaches “Organoids were transferred into a conical tube (Supplemental page e4, para 5),” corresponding to the claim limitations of d) obtaining a three-dimensional neuromuscular organoid from the non-supplemented serum-free cell culture medium.
With respect to claim 2, Martins teaches the non-supplemented serum-free cell culture medium (neurobasal medium) is at least one of Dulbecco's Modified Eagle Medium comprising Ham's F12 medium or neurobasal medium (Supplemental page e1-2, see key resource table).
With respect to claim 3, Martins teaches the activator of a growth factor signaling pathway includes an activator of the fibroblast growth factor signaling pathway, an activator of the hepatocyte growth factor signaling pathway, and an activator of the insulin-like growth factor signaling pathway (Supplemental see page e3, para. 4-5) as discussed above.
With respect to claim 4, Martins teaches the first differentiation medium is a serum-free cell culture medium supplemented with a ROCK inhibitor, basic fibroblast growth factor, insulin-like growth factor, and hepatocyte growth factor (Supplemental see page e3, para 4-5) as discussed above.
With respect to claim 5, Martins teaches the second differentiation medium is a serum free cell culture medium supplemented with insulin-like growth factor and hepatocyte growth factor (Supplemental see page e3, para 4-5) as discussed above.
With respect to claim 6, Martins teaches “After day 4 the organoids were maintained in NB medium without the addition of growth factors” (i.e., related to claim 1c changing into the non-supplemented serum-free cell culture medium). It is noted that the cells are cultured in a 96-well plate and are undergone media-change once every two days (see Supplemental page e3, last para, starting at Day 0, changing media at Day 2 and Day 4). Accordingly, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have adopted the media-change schedule of once every two days before Day 10 as suggested by Martins with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so since Martins has reduced to practice the culture method (i.e., changing media every two days in a small container of a 96-well plate) in order to replenish with fresh culture medium to support the growth of the cells.
Furthermore, Martins teaches “On day 10 the organoids were transferred in 60mm dishes (Corning) in 5 mL of medium and after 1 month in 100mm dishes (Corning) with 12 mL NB medium” (Supplemental page e3, last para). It is noted that the cells are cultured in a larger container with a larger volume of medium after Day 10. Accordingly, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have adopted the media-change schedule of once every 2 days or once every 2 to 5 days after Day 10 with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so since Martins has reduced to practice the culture method of changing media every 2 days and since Martins uses a larger container with a larger volume of medium that allows longer interval between media changes.
With respect to claim 7, Martins teaches during the whole period organoids were maintained on an orbital shaker rotating at 75 rpm, corresponding to the claim limitation wherein the method is carried out under agitation.
With respect to claim 8, Martins teaches “the first day the cells were plated in neurobasal (NB) medium supplemented with 10uM Rock inhibitor (Tocris Bioscience), 3uM CHIR99021 (Tocris Bioscience) and 40ng/ml bFGF (Peprotech)” (Supplemental page e3, para “In vitro generation of NMPs from human pluripotent stem cells”), thus teaches the NMPs are obtained by providing a second cell culture comprising pluripotent stem cells and cultivating the pluripotent stem cells in a first cultivation medium comprising a serum-free cell culture medium supplemented with at least one of a ROCK inhibitor, an activator of β-catenin signaling pathway, and an activator of a growth factor signaling pathway.
With respect to claims 9-11, Martins teaches neurobasal (NB) medium supplemented with CHIR99021 (see above), corresponding the first cultivation medium comprises a serum-free cell culture medium supplemented at least with an activator of β-catenin signaling pathway (i.e., CHIR99021), which is an inhibitor of glycogen synthase kinase 3 activity, which has a chemical name of 6-[[2-[[4-(2,4-Dichlorophenyl)-5-(5-methyl-1 H-imidazol-2-yl)-2-pyrimidinyl] amino]ethyl]amino ]-3-pyridinecarbonitrile.
With respect to claims 12-13, Martins teaches the medium comprises bFGF (see above), thus teaches the activator of a growth factor signaling pathway is an activator of fibroblast growth factor signaling pathway, that is a fibroblast growth factor.
With respect to claims 14-15, Martins teaches “The next day Rock inhibitor was removed and the cells were maintained in NB medium supplemented with 3uM CHIR99021 and 40ng/ml bFGF (Peprotech) until day 3” (Supplemental page e3, para “In vitro generation of NMPs from human pluripotent stem cells”), thus teaches the first cultivation medium is changed against a second cultivation medium 1 to 3 days after cultivation starts, and the second cultivation medium includes a serum-free cell culture medium supplemented with at least one of an activator of β-catenin signaling pathway and an activator of a growth factor signaling pathway. Since the only difference between the two media is the removal of the ROCK inhibitor, Martins teaches the second cultivation medium corresponds to the first cultivation medium except that the first cultivation medium contains a ROCK inhibitor but the second cultivation medium does not contain a ROCK inhibitor.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Rejections over Gouti
Claims 1-2 and 8-15 are rejected under 35 U.S.C. 103 as being unpatentable over Gouti et al., (PLoS Biol. 2014; 12(8): e1001937, p. 1-15. Cited in IDS 01/10/2023) in view of Petersen (“Growing mini-organs from stem cells”, published on June 04, 2019. downloaded from https://www.mdc-berlin.de/news/news/growing-mini-organs-stem-cells, downloaded on 2/9/2026, p. 1-5).
With respect to claim 1, it is noted that claim 1, steps (a)(i), (b)(i) and (c) are directed to cultivating NMPs in a non-supplemented serum-free cell culture medium for 1 day each in steps (a) and (b). Accordingly, under a broadest reasonable interpretation, claim 1 is interpreted as a method comprising providing and cultivating disease-specific NMPs in the same non-supplemented serum-free cell culture medium for 2 days (i.e., cultivating for 1 day in the first medium in (a)(i), cultivating for 1 day in the second medium (b)(i) that encompasses the same medium as the first medium in (a)(i), replacing to a third medium in (c) that encompasses the same medium as the first medium in (a)(i)), and obtaining a 3D neuromuscular organoid in (d).
Gouti teaches obtaining neuromesodermal progenitor cells (NMPs) from directed differentiation of human pluripotent stem cells (see e.g., p. 7, left col, last para “Directed Differentiation of Human ES Cells to NMPs”). Gouti teaches after treatment from D0-D3, “up to ~80% of cells co-expressed SOX2 and BRACHYURY (Figure 5B, Figure S4B). We also observed the spontaneous upregulation of paraxial mesoderm/somite markers (TBX6, MSGN1, MEOX1). (Figure S5C).” (p. 7, left col, last para – right col, para 1, also see Fig S5B for images of TBX6 expression). Thus, Gouti teaches a method comprising providing a first cell culture comprising NMPs, wherein 30% to 90% of the NMPs co-express BRACHYURY/SOX2 and likely 10% to 70% of the NMPs co-express TBX6.
Gouti teaches cultivating the NMPs in a basal medium from D3 to D6 (see Fig 5A middle bar, it is noted that culturing PSCs from D0-D3 generates NMPs as discussed above). Gouti teaches the basal medium is serum free media without additional factors (p. 7, right col, para 2) which is N2B27 alone (p. 12, left col, para 2). Thus, Gouti teaches an in vitro method comprising providing NMPs (culturing PSCs from D0-D3) and cultivating the NMPs in a non-supplemented serum-free cell culture medium (i.e., N2B27 medium) for at least 2 days (i.e., from D3 to D6).
Regarding obtaining a 3D neuromuscular organoid in (d), it is noted that this is directed to the result of the cultivation steps in (a), (b) and (c). Since Gouti teaches the same method steps (a), (b) and (c) as claimed (see above), these method steps would have inherently produced the identical results as claimed. See MPEP 2112. II.
However, Gouti is silent on providing and cultivating disease-specific NMPs.
Petersen teaches the neuromuscular organoids hold great potential for studying development of the neuromuscular system and diseases (p. 2, section “To study and treat disease”). Petersen teaches to grow the organoids, Gouti’s lab works with induced pluripotent stem cells (iPSCs) derived from a patient, to ultimately develop into the spinal cord neurons and skeletal muscle, and growing into a three-dimensional, self-organizing tissue structure in a petri dish (p. 3, section “It starts with stem cells”) and “Importantly, these cells, whatever they become, still carry the mutations of the patient’s DNA, allowing the scientists to more easily study the patient’s disease in the lab. For example, testing how the patient’s cells respond to certain drugs or treatments” (p. 3, section “Patient specific”). Thus, Petersen, referring to the work of Gouti’s lab, teaches differentiating a patient-derived iPSC (i.e., disease-specific iPSCs) into neuromuscular organoids that allows individualized drug screening.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method comprising cultivating wildtype human PSC-derived NMPs for generating neuromuscular organoids disclosed by Gouti, by substituting with disease-specific iPSC as suggested by Petersen with a reasonable expectation of success. Since Petersen, referring to the work of Gouti’s lab, teaches differentiating a patient-derived iPSC (i.e., disease-specific iPSCs) into neuromuscular organoids allows individualized drug screening (p. 3, section “Patient specific”), one of ordinary skill in the art would have had a reason to substitute with a disease-specific iPSC to generate disease-specific NMPs in order to obtain disease-specific neuromuscular organoids for screening drugs or treatment.
With respect to claim 2, as stated supra, Gouti teaches the non-supplemented serum-free medium is N2B27 (p. 12, left col, para 2), and teaches “this medium comprised Advanced Dulbecco’s Modified Eagle Medium F12 (Gibco) and Neurobasal medium (Gibco) (1:1)” (p. 11, last para).
With respect to claim 8, Gouti teaches the human ESCs are plated “in N2B27 medium supplemented with 3 uM CHIR99021 / 20 ng/ml bFgf and Y-27632 (10 uM). The medium was replaced the following day with fresh N2B27 containing the same components minus the ROCK inhibitor.” (p. 12, left col, para 2), thus teaches the NMPs are obtained by providing a second cell culture comprising pluripotent stem cells and cultivating the pluripotent stem cells in a first cultivation medium comprising a serum-free cell culture medium supplemented with at least one of a ROCK inhibitor (i.e., Y-27632), an activator of β-catenin signaling pathway (i.e., CHIR99021), and an activator of a growth factor signaling pathway (i.e., bFgf).
With respect to claims 9-11, Gouti teaches the N2B27 medium supplemented with CHIR99021 (see above), corresponding the first cultivation medium comprises a serum-free cell culture medium supplemented at least with an activator of β-catenin signaling pathway (i.e., CHIR99021), which is an inhibitor of glycogen synthase kinase 3 activity, which has a chemical name of 6-[[2-[[4-(2,4-Dichlorophenyl)-5-(5-methyl-1 H-imidazol-2-yl)-2-pyrimidinyl] amino]ethyl]amino ]-3-pyridinecarbonitrile.
With respect to claims 12-13, Gouti teaches the medium comprises bFgf (see above), thus teaches the activator of a growth factor signaling pathway is an activator of fibroblast growth factor signaling pathway, that is a fibroblast growth factor.
With respect to claims 14-15, Gouti teaches “The medium was replaced the following day with fresh N2B27 containing the same components minus the ROCK inhibitor.” (p. 12, left col, para 2), thus teaches the first cultivation medium is changed against a second cultivation medium 1 to 3 days after cultivation starts, and the second cultivation medium includes a serum-free cell culture medium supplemented with at least one of an activator of β-catenin signaling pathway and an activator of a growth factor signaling pathway. Since the only difference between the two media is the removal of the ROCK inhibitor, Gouti teaches the second cultivation medium corresponds to the first cultivation medium except that the first cultivation medium contains a ROCK inhibitor but the second cultivation medium does not contain a ROCK inhibitor.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Provisional Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 17/372,160 (‘160) in view of Petersen (“Growing mini-organs from stem cells”, published on June 04, 2019. downloaded on 2/9/2026, downloaded from https://www.mdc-berlin.de/news/news/growing-mini-organs-stem-cells, p. 1-5). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims recite a method for generating a three-dimensional neuromuscular organoid in vitro by cultivating NMPs in serial differentiation media. Copending claims recite most of the limitations in instant claims 1-15.
However, copending claims are silent on providing and cultivating disease-specific NMPs.
Petersen teaches the neuromuscular organoids hold great potential for studying development of the neuromuscular system and diseases (p. 2, section “To study and treat disease”). Petersen teaches to grow the organoids, Gouti’s lab works with induced pluripotent stem cells (iPSCs) derived from a patient, to ultimately develop into the spinal cord neurons and skeletal muscle, and growing into a three-dimensional, self-organizing tissue structure in a petri dish (p. 3, section “It starts with stem cells”) and “Importantly, these cells, whatever they become, still carry the mutations of the patient’s DNA, allowing the scientists to more easily study the patient’s disease in the lab. For example, testing how the patient’s cells respond to certain drugs or treatments” (p. 3, section “Patient specific”). Thus, Petersen, referring to the work of Gouti’s lab, teaches differentiating a patient-derived iPSC (i.e., disease-specific iPSCs) into neuromuscular organoids that allow individualized drug screening.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method comprising cultivating NMPs for generating neuromuscular organoids recited in copending claims, by choosing disease-specific iPSC derived NMPs as suggested by Petersen with a reasonable expectation of success. Since Petersen, referring to the work of Gouti’s lab, teaches differentiating a patient-derived iPSC (i.e., disease-specific iPSCs) into a 3D neuromuscular organoid allows individualized drug screening (p. 3, section “Patient specific”), one of ordinary skill in the art would have had a reason to choose a disease-specific iPSC to generate disease-specific NMPs in order to obtain disease-specific neuromuscular organoids for screening drugs or treatment.
Since the instant application claims are obvious over cited application claims, in view of Petersen, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Claims 1-6 and 8-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-12 of copending Application No. 18/335,765 (‘765) in view of Petersen (“Growing mini-organs from stem cells”, published on June 04, 2019. downloaded on 2/9/2026, downloaded from https://www.mdc-berlin.de/news/news/growing-mini-organs-stem-cells, p. 1-5) and Gouti et al., (PLoS Biol. 2014; 12(8): e1001937, p. 1-15. Cited in IDS 01/10/2023). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims of ‘765 recite an in vitro method of generating a neuro-muscular junction cell culture model, comprising cultivating a first cell culture comprising PSCs for at least 3 days in a first culture medium comprising a WNT pathway activator and FGF (reference claim 1, related to instant claims 8-10, 12-13 and claim 1 (a) for providing NMPs derived from PSCs), replacing by a second culture medium comprising growth factors such as FGF, HGF and IGF and cultivating for at least 3 days (reference claim 1, related to instant claims 1 (a) and 3-5), replacing by a culture medium comprising HGF and IGF and replacing the culture medium by a medium suitable for maintenance of the cell culture model (reference claim 3, related to instant claim 1 steps (b), (c) and claim 2. It is noted the medium suitable for maintenance of the cell culture model encompasses a non-supplemented serum-free cell culture medium suitable for maintenance of the organoid culture, such as DMEM F12). Reference claim 5 recites a method of culturing cells in seven media with cultivation time of 1 day to 5 days each, corresponding to the media-change interval recited in instant claim 6. Reference claim 12 recites the first cell culture comprises PSCs of a patient that has been diagnosed with a myopathy or motor-neuron disease, corresponding to the disease-specific PSC-derived NMPs in instant claim 1. It is noted that the claimed neuro-muscular junction cell culture model in reference application encompasses a 3D neuromuscular organoid in the instant claims.
However, copending claims are silent on generating a three-dimensional neuromuscular organoid.
Petersen teaches the neuromuscular organoids hold great potential for studying development of the neuromuscular system and diseases (p. 2, section “To study and treat disease”). Petersen teaches to grow the organoids, Gouti’s lab works with induced pluripotent stem cells (iPSCs) derived from a patient, to ultimately develop into the spinal cord neurons and skeletal muscle, and growing into a three-dimensional, self-organizing tissue structure in a petri dish (p. 3, section “It starts with stem cells”), “allowing the scientists to more easily study the patient’s disease in the lab. For example, testing how the patient’s cells respond to certain drugs or treatments” (p. 3, section “Patient specific”). Thus, Petersen, referring to the work of Gouti’s lab, teaches differentiating a patient-derived iPSC (i.e., disease-specific iPSCs) into a 3D neuromuscular organoid that allows individualized drug screening.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method comprising generating a neuro-muscular junction cell culture model from patient-derived PSCs recited in the copending claims, by choosing the neuro-muscular junction model being a 3D neuromuscular organoid as suggested by Petersen with a reasonable expectation of success. Since Petersen, referring to the work of Gouti’s lab, teaches 3D neuromuscular organoids hold great potential for studying development of the neuromuscular system and diseases (p. 2, section “To study and treat disease”) and allows individualized drug screening (p. 3, section “Patient specific”), one of ordinary skill in the art would have had a reason to generate a 3D neuromuscular organoid by the recited method as suggested by Petersen in order to study development of the neuromuscular system and diseases and screen drugs or treatment.
However, copending claims are silent on the WNT signaling activator being CHIR99021 in instant claim 11, nor recite a second cultivation medium for culturing PSCs in instant claims 14-15.
Gouti teaches culturing human ESC to differentiate into NMPs. Gouti teaches the human ESCs are plated “in N2B27 medium supplemented with 3 uM CHIR99021 / 20 ng/ml bFgf and Y-27632 (10 uM). The medium was replaced the following day with fresh N2B27 containing the same components minus the ROCK inhibitor.” (p. 12, left col, para 2). Thus, Gouti teaches the WNT signaling activator being CHIR99021, that has the chemical name 6-[[2-[[4-(2,4-Dichlorophenyl)-5-(5-methyl-1 H-imidazol-2-yl)-2-pyrimidinyl] amino]ethyl]amino ]-3-pyridinecarbonitrile in instant claim 11, and teaches the first cultivation medium is changed against a second cultivation medium 1 to 3 days after cultivation starts, and the second cultivation medium includes a serum-free cell culture medium supplemented with at least one of an activator of β-catenin signaling pathway and an activator of a growth factor signaling pathway. Gouti teaches the second cultivation medium corresponds to the first cultivation medium except that the first cultivation medium contains a ROCK inhibitor but the second cultivation medium does not contain a ROCK inhibitor, thus teaches instant claims 14-15.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method comprising generating a 3D neuromuscular organoid from patient-derived PSCs recited in the copending claims in view of Petersen, by substituting with a culture method for differentiating PSCs into NMPs as suggested by Gouti with a reasonable expectation of success. Since Gouti has reduced to practice a method for differentiating PSCs into NMPs which is equivalent to the first cell culture in reference claims (and the second cell culture in instant claims 8-15), one of ordinary skill in the art would have had a reason to substitute with the method of Gouti to differentiate the PSCs into NMPs in order to generate a 3D neuromuscular organoid.
Since the instant application claims are obvious over cited application claims, in view of Petersen and Gouti, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Conclusion
No claims are allowed.
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/JIANJIAN ZHU/Examiner, Art Unit 1631