DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s election without traverse of Group I and the combination of BRINP1, CDKN1A, FAM83D, FANCD2, GEM, PLK2, and SAPCD2 in the reply filed on June 1, 2026 is acknowledged.
Claims 3-8, 11, 13-16, 20-23, and 88-98 are currently pending.
Claims 5-6, 11, 14, 88-98 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on June 1, 2026.
The claims have been examined to the extent that the claims read on the elected combination of genes (BRINP1, CDKN1A, FAM83D, FANCD2, GEM, PLK2, and SAPCD2). The additionally recited genes have been withdrawn from consideration as being directed to non-elected subject matter. Prior to allowance of the claim, any non-elected subject matter that is not rejoined with any allowed elected subject matter will be required to be removed from the claims.
Claim Rejections - 35 USC § 101
3. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 3-4, 7-8, 13, 16, and 20-23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims recite a judicial exception that is not integrated into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The claim analysis is set forth below.
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite a law of nature.
The claims recite a correlation between the expression level of BRINP1, CDKN1A, FAM83D, FANCD2, GEM, PLK2, and SAPCD2 and likelihood of engraftment in the brain region of a subject. This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
The instant claims recite abstract ideas.
The claims recite a step of “applying” the gene expression levels as input to a process configured to predict if the population of neuronal progenitor cells will engraft in a brain region of a subject following implantation of the population of neuronal progenitor cells into the brain region, wherein the predicting is based on the gene expression levels, and the process comprises a machine learning model (clm 3). Machine learning falls within the category of mathematical concepts because it often relies on mathematical algorithms. Mathematical concepts are abstract ideas.
The claims recite a step of “selecting” the population of neuronal progenitor cells for implantation in the subject if the population of neuronal progenitor cells are predicted to engraft (clms 3, 16). The “selecting” step broadly encompasses an activity that can be performed in the human mind. The “selecting” could be performed by reading a laboratory report on thinking about which populations of neuronal progenitor cells were predicted to engraft. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgment, opinions) are considered to be abstract ideas.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological
environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
In addition to the judicial exceptions claim 3 recites obtaining gene expression levels of a plurality of genes for one or more cells of a population of neuronal progenitor cells, wherein the population of neuronal progenitor cells is from a culture of cells differentiated from pluripotent stem cells under conditions to neurally differentiate the cells. Claim 16 further recites harvesting the cells. Claims 22-23 further comprises differentiating the culture of cells comprising the population of neuronal progenitor cells. These steps are NOT considered to integrate the judicial exception into a practical application because they merely add insignificant extra-solution activity to the judicial exceptions. The claims do not apply the judicial exceptions by engrafting the selected population of cells predicted to engraft.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition to the judicial exceptions claim 3 recites obtaining gene expression levels of a plurality of genes for one or more cells of a population of neuronal progenitor cells, wherein the population of neuronal progenitor cells is from a culture of cells differentiated from pluripotent stem cells under conditions to neurally differentiate the cells. Claim 16 further recites harvesting the cells. Claims 22-23 further comprises differentiating the culture of cells comprising the population of neuronal progenitor cells. These steps do not amount to significantly more because they simply append well understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions.
The prior art also demonstrates the well understood, routine, conventional nature of additional elements because it teaches that the additional elements are well known or commercially available.
For example Sareen (J Comp Neurol. Author manuscript; available in PMC: 2015 Aug 15. Published in final edited form as: J Comp Neurol. 2014 Apr 12;522(12):2707–2728) teaches that human neural progenitor cells generated from induced pluripotent stem cells can survive, migrate, and integrate in the rodent spinal cord (abstract). Sareen teaches how to generate neuronal progenitor cells from pluripotent stem cells (pages 4-5, 9). Sareen further teaches that as the plated iNPCsAD appeared morphologically like astrocytes, we wanted to further establish how similar these cultures were to neural progenitors or astroglia. To do this, we assessed gene expression of multiple astrocyte markers. Analysis by qRT-PCR showed iNPCsAD had increased levels of GFAP mRNA compared to iPSC and EZ spheres, however, the other markers were expressed in similar levels to EZ spheres (page 10). Sareen further teaches for differentiation to astrocytes, iNPCsAD harvested with TrypLE were plated on poly-l ornithine/Matrigel coated glass coverslips at 25000 cells/cm2 in NIM for 7–21 days (page 5).
Additionally Gonzalez (Scientific Reports 3:1463 March 15, 2013 pages 1-5) discloses derivation of NSC from hPSC (page 1, 4). Gonzalez teaches they performed microarray analysis to identify transcripts that are differentially expressed between pairs of cell types (hPSC vs Substantia Nigra, hPSC vs NSC, and hPSC vs Dopaminergic neurons) (page 4-5).
Further Kirkeby (Cell Stem Cell 20 135-148 1/5/2017) teaches that they took an unbiased approach to identify in vitro markers that can predict successful graft outcome in vivo of ventral mesencephalon (VM) progenitors by sequencing more than 30 batches of human embryonic stem cell (hESC)-derived VM patterned cells with known graft outcomes (page 136). Kirkeby teaches that differentiation protocols giving rise to VM progenitors from hPSC that mature and function after transplantation were known (page 135).
It is noted that the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For the reasons set forth above the claims are not directed to patent eligible subject matter.
Improper Markush Grouping Rejection
4. Claims 3-4. 7-8, 16, 20-23 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature.
The claims recite the following Markush group: the plurality of genes comprises one or more of AC 104083.1, ACE, ACSL1, ACSS3, ADSS, AFAP1, ANLN, ANP32A, ANXA11, APBA1, ARHGDIG, ARL8A, ASPH, ASPM, AURKA,…(see clm 3). The Markush group is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
It is first noted that MPEP 706.03(y) states that “A Markush claim may be rejected under judicially approved “improper Markush grouping” principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an “improper Markush grouping” if either: (1) the members of the Markush group do not share a “single structural similarity” or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)). “ Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class (prong 1) and the members of a Markush group share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent (prong 2).
The phrase “significant structural element is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity.
A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved” (see MPEP 706.03(y)IIA).
Herein, the recited alternative species do not share a single structural similarity, as each gene has a different chemical structure in that it consists of a different nucleotide sequence. The only structural similarity present is that all of the genes comprise nucleotides. The fact that the genes comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising nucleotides alone is not essential to the asserted common property of being predictive of engraftment of NPC. Accordingly, while the different genes are asserted to have the property of being predictive of engraftment NPC, they do not share a substantial structural similarity essential to this activity.
Further, the recited genes do not belong to a chemical or art-recognized class because there is no expectation from the knowledge in the prior art that genes behave in the same manner and can be substituted for one another with the same intended result achieved. There is no evidence of record to establish that it is clear from their very nature that the recited genes possess the common property of being predictive of engraftment of NPC.
The claims recite that the genes have the common property of being predictive of engraftment of NPC. However, the specification provides numerous tables (E1-E8) with genes that are correlated with different things. For example Table E1 contains genes that are upregulated in engrafting samples compared to samples that were known not to engraft. each directed to a different condition. However Table E2 contains genes that are upregulated in developmental maturity and Table E3 contains genes that are downregulated in developmental maturity. Thus, the genes listed in claim 3 which are present in different Tables in the specification do not all share a common use/function.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
It is noted for the record that claim 13 has not been included in this rejection because it requires the elected combination of genes. This rejection could be overcome by amending claim 3 to remove the alternative language and require the elected combination of genes. For example:
“wherein the plurality of genes comprises each of BRINP1, CDKN1A, FAM83D, FANCD2, GEM, PLK2, and SAPCD2”
5. Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Shen can be reached at 571-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682
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