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 .
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-11 in the reply filed on 06/12/2026 is acknowledged. The traversal is found persuasive and the groups are hereby rejoined. Claims 1-20 are under examination
Claim Rejections - 35 USC § 112
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 1-20 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 the claimed methods (claims 1-14) wherein 1) the neuronal progenitors are embryonic MGE neuronal progenitors or 2) the primary cells are embryonic post-mitotic somatostatin-positive interneurons and wherein 3) the human brain organoid is a cortical brain organoid and a chimeric human embryonic cortical brain organoid made by the method, does not reasonably provide enablement for 1) any type of neuronal progenitor, 2) use of post-mitotic somatostatin interneurons to obtain at least 80% PV+ interneurons (claim 11), or 3) any type of brain organoid other than a cortical brain organoid or a chimeric organoid made by any other method. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). 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 are discussed below.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Nature of the Invention-The invention relates to a method of using a human brain slice or cortical brain organoid to direct the differentiation of mouse medial ganglionic eminence ( MGE) progenitors or trans-differentiate mouse differentiated post-mitotic somatostatin-positive progenitors into parvalbumin-positive (PV+) interneurons (INs). MGE progenitors can differentiate into distinct PV+ and somatostain-positive (SST+) interneuron populations. PV and SST are terminal markers of distinct interneuron populations (para 119).
Breadth of the Claims-The claims are drawn to a method of differentiating neuronal progenitors into PV+ INs using either human brain organoid or a primary brain slice of human origin. The claims are broad with regard to the type of neuronal progenitor cell used (there are multiple types) and with regard to the type of brain organoid (they can be derived from a variety of parts of the brain). As well, claim 1 is drawn to use opf primary neuronal progenitors while dependent claim 5 includes differentiated, non-progenitor cells. The specification does teach trans-differentiating these differentiated cells but it is noted that they are not progenitors; they are already differentiated.
Guidance in the Specification-The specification, beginning at para 106, teaches differentiation of mouse MGE progenitors in organotypic mouse and human embryonic brain slices. The mouse progenitors form predominantly PV+ interneurons (Ins) when cultured in human brain slices. In mouse brain slices, however, they form a smaller amount of SST Ins and predominantly double negative cells.
Beginning at para 108, the system is shifted to a human cortical brain organoid where results consistent with the brain slice experiments were obtained. Para 117 discusses generating mouse brain organoids and culture of mouse MGE in them and some (~29%) SST+ cells were obtained with ~1% PV+ and ~67% double negative. Thus, mouse MGE progenitor cells differentiate into PV+ Ins in human brain slices and human cortical organoids but not in either derived from mouse.
At para 127, it is discussed how organoids formed from other brain sections affect differentiation of MGE progenitors. Human MGE organoids led PGE progenitors to be SST+ ~52% while no PV+ cells were obtained and ~1% double positive cells were obtained. Use of thalamic organoids resulted in death of the MGE progenitors. Thus, the specification supports that only cortical brain organoids are enabled for derivation of the PV+ INs.
Reprogramming of differentiated SST+ INs is discussed at para 131-133. SST+Ins were transplanted into human cortical organoids and only ~29% were found to be SST+ at 14 DPT with ~25% PV+ and ~31% double positive. It is noted that this finding fails to support the embodiment of claim 11 wherein post-mitotic somatostatin-positive INs are used (claim 5) result in at least 80% of the population being PV+ (claim 11). Therefore, claim 11 should be limited in breadth to where the at least 80% refers only to the method using MGE neuronal progenitors and not differentiated SST+ INs.
State of the Art-The state of the art at time of filing was that there are many different subtypes of neuronal progenitors. Martinez-Cerdeno (2018, Frontiers in Neuroanatomy, 12:104, doi: 10.3389/fnana.2018.00104) teaches that NPCs are characterized based on their location in the brain. Morphology, gene expression profile, temporal distribution and function. It is also taught that embryonic NPCs have more potential than adult NPCs. Kim (Stem Cells. 2014 July ; 32(7): 1789–1804. doi:10.1002/stem.1704.) taught that MGE progenitors mostly generate PV-expressing or SST-expressing INs while the Caudal Ganglionic Eminence (CGE) progenitor cells mostly generate Calretinin-expressing INs, highlight the distinction between the subtype of neural progenitor cell and their fate potential. Thus, progenitor cells are fate-restricted to some degree and are not all capable of differentiating into the same cell types.
Unpredictability and Experimentation-The specification and art establish a level of unpredictability with regard to transplantation of neural precursors into primary brain slices and organoids that would render an undue amount of experimentation to carry out the full breadth of the claims. The conditions to obtain PV+ INs all include human cortical primary tissues or human cortical organoids as it was found that non-cortical organoids and mouse slices and organoids did not provide the same result. As well, the art has established differences and distinctions between subtypes of neuronal progenitors as well as embryonic versus adult-derived neuronal precursors. It would require an undue amount of experimentation to determine which other neuronal progenitor populations beyond mouse embryonic MGE neuronal progenitors would lead to the claimed enriched population of PV+ interneurons.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5-9 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 5 is unclear as it limits the neuronal progenitor population of claim 1 to include differentiated (non-progenitor), post-mitotic somatostatin-positive interneurons. Thus, this embodiment falls outside the breadth of claim 1. Claims 6-9 depend from claim 5 and are unclear based on their dependency.
Conclusion
The prior art currently of record and not relied upon is considered pertinent to applicant's disclosure. US 2019/0002835 discusses am organoid complex can be used as an in vitro differentiation system for developing differentiated neuronal lineagesfrom distinct regions of the brain but does not discuss how to use the system to obtain an enriched population of PV+ INs.
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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