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 .
Election/Restrictions
2. Applicant’s election without traverse of Group III and the species of the combination of the NKG7, GNLY, FGFBP2, GZMH, CTSW, CCL5, CD8A, KLRD1, PRDM1, ZEB2, S100A8, S100A9, S100A12, LYZ, LST1, FCN1, TYROBP, FCER1G, AIF, CTSS,
CYBB, SPI1, HLA-DRA, STAT1, IFITM2, and LY6E genes in the reply filed on 01 June 2026 is acknowledged.
Claim Status
3. Claims 14 and 54-60 are pending.
Claims 56 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 14, 54, 55 and 57-60 read on the elected invention and have been examined herein. The claims have been examined to the extent that they read on the elected species of the combination of the 26 genes. It is noted that claims 14, 54 and 57-60 encompass the non-elected species of one or more genes from Table 2 and combinations of genes other than the elected combination of the 26 genes. Prior to the allowance of claims, any non-elected subject matter which has not been rejoined with the elected subject matter will be required to be removed from the claims.
Objection to Drawings / Objection to the Specification
4. The drawings are objected to under 37 CFR 1.83(a). The specification describes several of the figures in terms of particular colors. For example, at para [0035], Fig. 17D is described as “Nodes are colored by cell-type and shaped by their pathway category: Blue edges” and 17E as “Colors based on node linkages connecting a microbe (orange).” Note that paragraph numbering herein is with respect to the published application. However, the figures have been filed in black and white. Thus, the description of the figures in the specification is not consistent with the drawing and the specification is thereby also objected to.
If the drawings are intended to be in black and white, the specification should be amended to delete the reference to the recited colors. Alternatively, corrected drawing sheets in compliance with 37 CFR 1.121(d) are required. Note that color drawings are only accepted on rare occasions when they are the only practical medium by which to disclose the subject matter to be patented. See MPEP 608.02(VIII).
Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
If color photographs or color drawings are submitted, it is noted that color photographs and color drawings are not accepted unless a petition filed under 37 CFR 1.84(a)(2) is granted.
A petition for color drawings must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via EFS-Web or three sets of color drawings or color photographs, as appropriate, if not submitted via EFS-Web, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Appropriate correction is required.
Claim Rejections - 35 USC § 101
5. 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 14, 54, 55 and 57-60 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a law of nature / natural phenomenon, and/or an abstract idea without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Applicant' s attention is directed to MPEP 2106 “Patent Subject Matter Eligibility” which discusses the Alice/Mayo two-part test for evaluating subject matter eligibility.
Regarding Step 1 of the subject matter eligibility test set forth at MPEP 2106III, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of a law of nature. The claims recite the correlation between gene expression levels and a T cell being infection microenvironment reactive or tumor microenvironment reactive. As in Mayo Collaborative Services v. Prometheus, the recited relationship is a natural phenomenon that exists apart from any human action. See also Cleveland Clinic Foundation v. True Health Diagnostic, LLC, 2018-1218 (Fed Cir. 2019) which states that “The re-phrasing of the claims does not make them less directed to a natural law.”
The claims also recite the judicial exception of an abstract idea and particularly mental processes.
MPEP 2106.04(a) states that the enumerated groupings of abstract ideas include:
“1) Mathematical concepts – mathematical relationships, mathematical formulas or equations, mathematical calculations (see MPEP § 2106.04(a)(2), subsection I);…
3) Mental processes – concepts performed in the human mind (including an observation, evaluation, judgment, opinion) (see MPEP § 2106.04(a)(2), subsection III).”
The claims recite a step of “receiving” a single cell RNA sequencing dataset. As broadly recited, this step may be accomplished by reading information present in a database or report and does not require a transformative laboratory step of performing single cell RNA sequencing. Accordingly, the “receiving” step is an abstract idea / process
The claims require performing the step of “determining” the level of expression of the genes from a RNA sequencing dataset. Neither the specification nor the claims set forth a limiting definition for "determining" and the claims do not set forth how “determining” is accomplished. The broadest reasonable interpretation of the determining step is that this step may be accomplished by reading information in a database or report regarding the RNA sequencing dataset to thereby ascertain the level of expression of the genes in a sample obtained from a subject. Such “determining” thereby encompasses processes that may be performed mentally and thus is an abstract idea.
The claims further recite “classifying” the T cell from the comparing step and the preamble of the claims recites “determining T- cell microenvironment reaction in a cancer subject.” As broadly recited, the “classifying” and “determining T- cell microenvironment reaction” may be accomplished mentally and thus is an abstract step / process. The “classifying” and “determining T- cell microenvironment reaction” may alternatively be accomplished verbally. Such verbal communication is also abstract, having no particular concrete or tangible form.
The claims require performing a step of "comparing" expression levels to control levels using a random forest model. As broadly recited, the “comparing” step may be accomplished by critical thinking processes. Such “comparing” thereby encompasses only an abstract idea / process. The comparing using a random forest model can also be performed using pen and paper or using a generic computer with a software program. Note that the use of pen and paper or a generic computer or software program to implement an abstract idea does not itself impart patent eligibility.
As stated in MPEP 2106.04(a)(2) III “The courts do not distinguish between mental processes that are performed entirely in the human mind and mental processes that require a human to use a physical aid (e.g., pen and paper or a slide rule) to perform the claim limitation” and that “Nor do the courts distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer.”
Further, the use of a random forest model to compare expression levels constitutes a judicial exception of a mathematic concept.
See MPEP 2106.04I which states “mathematical formulas are considered to be a judicial exception as they express a scientific truth, but have been labelled by the courts as both abstract ideas and laws of nature.”
See also MPEP 2106.04(a)(2):
“A claim that recites a mathematical calculation, when the claim is given its broadest reasonable interpretation in light of the specification, will be considered as falling within the “mathematical concepts” grouping. A mathematical calculation is a mathematical operation (such as multiplication) or an act of calculating using mathematical methods to determine a variable or number, e.g., performing an arithmetic operation such as exponentiation. There is no particular word or set of words that indicates a claim recites a mathematical calculation. That is, a claim does not have to recite the word “calculating” in order to be considered a mathematical calculation. For example, a step of “determining” a variable or number using mathematical methods or “performing” a mathematical operation may also be considered mathematical calculations when the broadest reasonable interpretation of the claim in light of the specification encompasses a mathematical calculation.
Examples of mathematical calculations recited in a claim include:…
v. using an algorithm for determining the optimal number of visits by a business representative to a client, In re Maucorps, 609 F.2d 481, 482, 203 USPQ 812, 813 (CCPA 1979); and
vi. calculating the difference between local and average data values, In re Abele, 684 F.2d 902, 903, 214 USPQ 682, 683-84 (CCPA 1982).”
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). As discussed above, the receiving, determining, comparing and classifying steps are a judicial exception of an abstract idea and not something in addition to a judicial exception. The steps are also part of the data gathering process necessary to observe the judicial exception. These steps do not practically apply the judicial exception.
Regarding claim 59, this claim recites “further comprising treating the subject with a therapy that targets T-cells, if the T-cells from the subject are classified as tumor microenvironment reactive.” However, the treating step is conditional and need not occur in those instances in which the T cells are not classified as tumor microenvironment reactive, such as when the T cells are classified as infection microenvironment reactive. Accordingly, claim 59 encompasses methods wherein the T cells are not classified as tumor microenvironment reactive and thereby no treating step is performed. Thereby, the claim does not recite an additional element or step that integrates the judicial exception into a practical application.
Further, the treating step is recited at a very high degree of generality covering any therapy that targets T-cells for any purpose and which has any effect or outcome.
The broadly recited treating step does not constitute a practical application of the judicial exception. Rather, this is merely an “apply it” limitation.
Regarding specific treatments, see MPEP 2106.04(d)(2):
When determining whether a claim applies or uses a recited judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, the following factors are relevant.
a. The Particularity Or Generality Of The Treatment Or Prophylaxis
The treatment or prophylaxis limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s). For example, consider a claim that recites mentally analyzing information to identify if a patient has a genotype associated with poor metabolism of beta blocker medications. This falls within the mental process grouping of abstract ideas enumerated in MPEP § 2106.04(a). The claim also recites "administering a lower than normal dosage of a beta blocker medication to a patient identified as having the poor metabolizer genotype." This administration step is particular, and it integrates the mental analysis step into a practical application. Conversely, consider a claim that recites the same abstract idea and "administering a suitable medication to a patient." This administration step is not particular, and is instead merely instructions to "apply" the exception in a generic way. Thus, the administration step does not integrate the mental analysis step into a practical application….
b. Whether The Limitation(s) Have More Than A Nominal Or Insignificant Relationship To The Exception(s)
The treatment or prophylaxis limitation must have more than a nominal or insignificant relationship to the exception(s). For example, consider a claim that recites a natural correlation (law of nature) between blood glucose levels over 250 mg/dl and the risk of developing ketoacidosis (a life-threatening medical condition). The claim also recites "treating a patient having a blood glucose level over 250 mg/dl with insulin". Insulin acts to lower blood glucose levels, and administering insulin to a patient will reduce the patient’s blood glucose level, thereby lowering the risk that the patient will develop ketoacidosis. Thus, in the context of this claim, the administration step is significantly related to the recited correlation between high blood glucose levels and the risk of ketoacidosis. Because insulin is also a "particular" treatment, this administration step integrates the law of nature into a practical application. Alternatively, consider a claim that recites the same law of nature and also recites "treating a patient having a blood glucose level over 250 mg/dl with aspirin." Aspirin is not known in the art as a treatment for ketoacidosis or diabetes, although some patients with diabetes may be on aspirin therapy for other medical reasons (e.g., to control pain or inflammation, or to prevent blood clots). In the context of this claim and the recited correlation between high blood glucose levels and the risk of ketoacidosis, administration of aspirin has at best a nominal connection to the law of nature, because aspirin does not treat or prevent ketoacidosis. This step therefore does not apply or use the exception in any meaningful way. Thus, this step of administering aspirin does not integrate the law of nature into a practical application.
Also, the specification does not provide a limiting definition for what constitutes “treating” and does not require administering the therapy to the subject having cancer. To the extent that treating is intended to encompass prescribing a therapy that targets T-cells, such prescribing a therapy is an abstract step and not a non-patent-ineligible step.
See MPEP 2106.04(d)(2):
Examiners should keep in mind that in order to qualify as a "treatment" or "prophylaxis" limitation for purposes of this consideration, the claim limitation in question must affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition. An example of such a limitation is a step of "administering amazonic acid to a patient" or a step of "administering a course of plasmapheresis to a patient." If the limitation does not actually provide a treatment or prophylaxis, e.g., it is merely an intended use of the claimed invention or a field of use limitation, then it cannot integrate a judicial exception under the "treatment or prophylaxis" consideration. For example, a step of "prescribing a topical steroid to a patient with eczema" is not a positive limitation because it does not require that the steroid actually be used by or on the patient, and a recitation that a claimed product is a "pharmaceutical composition" or that a "feed dispenser is operable to dispense a mineral supplement" are not affirmative limitations because they are merely indicating how the claimed invention might be used.
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent-eligible. The claims do not require performing any specific, non-conventional transformative active process steps. Even if the claims did an require an active, laboratory steps) in which single cell RNA sequencing is performed, this step was well-known, routine and conventional in the prior art. This finding is evidenced by the teachings in the specification. See, e.g., para [0070]: “For example, gene expression can be detected and quantitated using RNA sequencing (RNA-seq), such as single cell RNA-seq (scRNA-seq) (see Stark, et al., Nat Rev Genet. 2019;20, 631-656; Haque, et al., Genome Med. 2017;9(75)).” See also Fan et al (U.S. 2016/145683; cited in the IDS) which teaches single cell RNA sequencing dataset from a sample, detecting microbial or viral nucleic acids in the dataset and identifying the microbe or the virus in the sample (e.g., para [0004], [0384], [0389], [0399], [0547] and [0556]).
See also MPEP 2106.05(d) II which states 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.
i. 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);
ii. 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);
iii. 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);…
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;…
vii. 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); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
Note that while the claims recite detecting the expression of particular genes, the identity of the genes is part of the judicial exception and not something in addition to the recited judicial exceptions. The claims do not require using a particular non-conventional reagent, such as a particular, non-conventional probe or primer consisting of or comprising a specific nucleotide sequence so as to add something ‘significantly more’ to the recited judicial exceptions.
To any extent that the claims require the use of a computer to perform the step of comparing expression levels using a random forest model, , see MPEP 2106.05(a) which states that ”Limitations that the courts have found not to be enough to qualify as “significantly more” when recited in a claim with a judicial exception include: i. Adding the words “apply it” (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer, e.g., a limitation indicating that a particular function such as creating and maintaining electronic records is performed by a computer, as discussed in Alice Corp., 134 S. Ct. at 2360, 110 USPQ2d at 1984 (see MPEP § 2106.05(f))”
Herein, the use of generic computer to calculate an EI does not add something “significantly more” to the recited judicial exceptions.
In Mayo v. Prometheus, the Supreme Court stated: "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
This is similar to the present situation wherein the additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide the inventive concept necessary to render the claims patent eligible. See also Genetic Technologies Ltd. v. Merial L.L.C. 818 F.3d at 1377, 1379 (Fed. Cir. 2016).
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.
Improper Markush Grouping Rejection
6. Claims 14, 54 and 57-60 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. See MPEP § 2117.
The Markush groupings of the 556 genes listed in Table 2, or the subset of genes of NKG7, GNLY, FGFBP2, GZMH, CTSW, CCL5, CD8A, KLRD1, PRDM1, ZEB2, S100A8, S100A9, S100A12, LYZ, LST1, FCN1, TYROBP, FCER1G, AIF, CTSS, CYBB, SPI1, HLA-DRA, STAT1, IFITM2, and LY6E, and combinations thereof are 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 2117 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 “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 2117IIA).
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 activity of having an expression level that is correlated with infection microenvironment reactive or tumor microenvironment reactive.. Accordingly, while the different genes are asserted to have the property of being correlated with infection microenvironment reactive or with tumor microenvironment reactive, 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 the 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 having an expression level that is indicative of infection microenvironment reactive or tumor microenvironment reactive.
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.
In particular, this rejection may be obviated by limiting claim 14 to the subject matter of claim 55 - for example, amending claim 14 to recite “…(ii) determining the expression level of a set of genes in the T-cells, the set of genes comprising each of NKG7, GNLY, FGFBP2, GZMH, CTSW, CCL5, CD8A, KLRD1, PRDM1, ZEB2, S100A8, S100A9, S100A12, LYZ, LST1, FCN1, TYROBP, FCER1G, AIF1, CTSS, CYBB, SPI1, HLA- DRA, STAT1,IFITM2, and LY6E; and (iii) comparing the expression level of the set of genes in the T-cells determined in (ii) to a control…”.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
7. 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 14, 54, 55, and 57-60 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.
A. Claims 14, 54, 55, and 57-60 are indefinite over the recitation of “genes of Table 2.” MPEP 2173.05(s) states:
“Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).”
Herein, the reference to the genes of Table 2 renders the claims incomplete.
B. Claims 14, 54, 55, and 57-60 are indefinite over the recitation of “comparing the expression level of the one or more genes of Table 2 in the T-cells to a control using a random forest model, thereby classifying the T-cells as infection microenvironment reactive or tumor microenvironment reactive.” It is unclear as to how comparing the expression level per se with any control necessarily results in classifying the T-cells as infection microenvironment reactive or tumor microenvironment reactive. Accordingly, it is unclear as to whether the claims require performing only the steps of receiving, determining the expression level and comparing the expression level or if the claims require a step of classifying the T-cells as infection microenvironment reactive or tumor microenvironment reactive. In the latter instance, it is unclear as to how the classifying is accomplished in the absence of a clear classifying step in the claims and the criteria for classifying the T-cell as infection microenvironment reactive as opposed to tumor microenvironment reactive, and vice versa.
Double Patenting
8. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 14, 54, 55 and 57-60 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4, 11 and 12 of copending Application No. 18/287,763 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the present claims and claims 4, 11 and 12 of ‘763 are both inclusive of a method of determining T-cell microenvironment reaction in a cancer subject, comprising: (i) obtaining a single cell RNA sequencing dataset for T-cells from the subject; (ii) determining the expression level of one or more of the genes of Table 2 in the T-cells; and (iii) comparing the expression level of the one or more genes of Table 2 in the T-cells to a control using a random forest model, thereby classifying the T-cells as infection microenvironment reactive or tumor microenvironment reactive. Note that claim 11 of ‘763 recites that the subject has cancer and claim 12 recites that the subject has pancreatic cancer.
The present claims differ from the claims of ‘763 only in that claim 4 of ‘763 recites “thereby classifying the individual T-cells” whereas the present claims recite “classifying the T-cells.” Additionally, claim 4 of ‘763 recites performing a step of sequencing nucleic acid molecules in individual T cells to determine the expression level of one or more genes of Table 2 in the individual T-cells, whereas the present claims recite obtaining RNA sequencing data for an individual T-cell. However, by performing a step of sequencing nucleic acid molecules in individual T-cells to determine RNA expression levels of one or more genes of Table 2, the claims of ‘763 necessarily generate single cell RNA sequencing data for individual T cells. Also since the claims of ‘763 recite the same steps of determining the expression level and comparing the expression level of the one or more genes of Table 2 in the T-cells to a control using a random forest model, the present claims and the claims of ‘763 necessarily also classifying T-cells, including individual T-cells, as infection microenvironment reactive or tumor microenvironment reactive.
Regarding present claims 54 and 55, the claims of ‘763 encompass determining the expression of each of the genes in Table 2, or any subcombination of the genes (i.e., “one or more genes of Table 2) and Table 2 includes each of the 26 genes listed in present claims 54 and 55.
Regarding present claim 57, claim 12 of ‘763 encompasses methods wherein the subject has pancreatic cancer.
Regarding present claim 58, the claims of ‘763 encompass methods wherein the T-cell is any type of T-cell. The claims of ‘763 do not particularly recite that the T-cell is a tumor-infiltrating T-cells.. However, when read in light of the specification of ‘763, it is clear that the T-cell is a tumor-infiltrating T-cell. Further, since in the method claimed in ‘763, the subject has cancer and the method determines if the T-cell is tumor microenvironment reactive, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have assayed the expression level of a T-cell that had infiltrated the tumor - i.e., a tumor-infiltrating T-cell - to accomplish the objective of classifying the T-cell as tumor microenvironment reactive.
Regarding present claim 59, the claims of ‘763 encompass the embodiment in which the T-cells from the subject are classified as infection microenvironment reactive and the subject is not treated with a therapy that targets T-cells. Accordingly, the method claimed in ‘763 in which the T-cells from the subject are classified as infection microenvironment reactive meets the limitations of claim 59.
Regarding claim 60, the claims of ‘763 do not recite the identity of the control sample. However, when read in light of the specification of ‘763, it is clear that the control can be an expression level of the genes in a subject or group of subjects known to have or to have had cancer, or from a subject or group of subjects known not to have cancer. Furthermore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used expression levels of the genes in a subject or group of subjects known to have or to have had cancer, or from a subject or group of subjects known not to have cancer as the control since the method is one in which the subject has cancer and the goal is to identify expression levels of the genes that are correlated with the classification of tumor microenvironment reactive.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 103
9. 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 (i.e., changing from AIA to pre-AIA ) 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.
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.
Claim(s) 14, 54, 55 and 57-60 are rejected under 35 U.S.C. 103 as being unpatentable over Griffiths et al (PNAS. 22 June 2020. 117: 16072-16082 and Supplementary Information p. 1-33, available via URL: < pnas.org/doi/suppl/10.1073/pnas.1918937117>).
Griffiths teaches a method comprising: sequencing a single T-cell from a sample from a subject by performing RNA sequencing of the single cell to generate a dataset for the T-cell(s); and comparing the expression level of each of the NKG7, GNLY, FGFBP2, GZMH, CTSW, CCL5, CD8A, KLRD1, PRDM1, ZEB2, S100A8, S100A9, S100A12, LYZ, LST1, FCN1, TYROBP, FCER1G, AIF, CTSS, CYBB, SPI1, HLA-DRA, STAT1, IFITM2, and LY6E genes in the dataset to that of a reference control using a random forest model (e.g., “Immune Cell Populations Identified Using scRNAseq Profiles” beginning at p. 16073, col. 2 and Fig. 3; “scRNAseq and Annotation “ at p. 16080; and Supplementary Information “Machine learning method” at p. 3 and Fig. S3 and S4).
Griffiths states (p. 16075, col. 1):
“The cell-type annotations were validated by comparing our transcriptional profiles and corresponding annotations with published studies of PBMCs and tumor-infiltrating immune cells. We found that 96.5% of T cells from the PBMC database and 94.1% of T cells from the tumor-infiltrating dataset were correctly predicted using a machine-learning classifier trained using our annotations (Fig. 3B and SI Appendix,Fig.S3).”
Note that RNAseq of the single T-cell determines the expression level of all transcriptionally active genes in the cell and thereby necessarily determines the expression level of each of the above genes Further, as shown in supplemental material of Griffiths, the RNA level of each of the NKG7, GNLY, FGFBP2, GZMH, CTSW, CCL5, CD8A, KLRD1, PRDM1, ZEB2, S100A8, S100A9, S100A12, LYZ, LST1, FCN1, TYROBP, FCER1G, AIF, CTSS, CYBB, SPI1, HLA-DRA, STAT1, IFITM2, and LY6E genes was determined in the T-cells. See partial printout below (full printout available at URL: < pnas.org/doi/suppl/10.1073/pnas.1918937117>, Dataset_SO2 (XLSX)).
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The present claims differ from the method of Griffiths in that Griffiths does not teach the limitation of “receiving a single cell RNA sequencing dataset for T-cells from the subject.” Rather, Griffiths teaches performing single cell RNA sequencing (scRNA-seq).
However, after generating the RNA sequencing dataset for the T-cells, the RNA sequencing dataset is necessarily provided to and thereby received by someone or by a computer to permit the practioner to compare the RNA sequencing dataset for the T-cells to a control dataset. Accordingly, the receiving step would have been an obvious addition to the method of Griffiths as part of a conventional workflow process. Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the methods of Griffiths so as to have received the RNA sequencing dataset for the T-cells of the subject from a different laboratory or entity. One would have been motivated to have done so in those instances in which different laboratories or entities performed the step of scRNA-seq of the T-cells and the step of comparing and analyzing the scRNA-seq dataset using a random forest model.
Regarding the final step of the claims of “thereby classifying the individual T-cells as infection microenvironment reactive or tumor microenvironment reactive,” since the modified method of Griffiths includes the same steps as that of present claim 14, the method necessarily has the same result of “thereby classifying the individual T-cells as infection microenvironment reactive or tumor microenvironment reactive.”
Regarding the preamble of the claims, by analyzing and classifying the T-cells present at the tumor, the method of Griffiths necessarily is one for determining a T-cell “microenvironment reaction.” Additionally, the preamble of the claim is not in agreement with or of the same scope as the final step of the claims. As set forth in MPEP 2111.02 II: “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention' s limitations, then the preamble is not considered a limitation and is of no significance to claim construction.” Herein, the preamble language is a statement of purpose and intended result and does not result in a manipulative difference in the method steps of the claims. Accordingly, the process steps are able to stand alone and the preamble limitation is not considered to materially distinguish the claimed method over the prior art.
Regarding claim 57, Griffiths teaches that the cancer subject is a subject having pancreatic cancer (e.g., p. 16073, col. 1 “Overview of Trial and Patient Cohort” and Supplementary Table S1 at p. 30).
Regarding claim 58, in the method of Griffiths, the T-cells are tumor-infiltrating T-cells (e.g., p. 16075, col. 1, Fig. 3B and S3).
Regarding claim 59, this claim recites treating the subject only if the T-cells from the subject are classified as tumor microenvironment reactive. Claim 59 includes the embodiment of not treating the subject if the T-cells from the subject are not classified as tumor microenvironment reactive. Griffiths teaches a method that does not classify the T-cells from the subject as tumor microenvironment reactive and which does not further treat the subject and thereby meets the limitations of claim 59.
Regarding claim 60, in the method of Griffiths, the control is an expression level of the genes in subjects known not to have cancer or the control is an expression level of the genes in subjects known to have cancer (e.g., “Immune Cell Populations Identified Using scRNAseq Profiles” beginning at p. 16073 to p. 16075; Fig. 3 and Fig. S3).10. Claim(s) 14, 54, 55 and 57-60 are rejected under 35 U.S.C. 103 as being unpatentable over Pan et al (J Hematology & Oncology. 2019. 12:124, p. 1-18) in view of Pouyan et al (Bioinformatics. 2018. 34: i79-i88).
Pan teaches a method comprising: sequencing a single T-cell from a sample from a subject by performing RNA sequencing of the single cell to generate a dataset for the T-cell(s); and comparing the expression level of each of the genes in the dataset to that of a reference control.. (e.g., p. 4 “Single-Cell RNA sequencing”, “Data preprocessing with Seurat package” and “Cluster specific gene identification and marker-based classification”; p. 8 “Composition of tumor-infiltrating immune cell
subpopulations identified by single-cell RNA-seq”; and p. 11 “Changes in CD8+ T cells”).
Pan states (p. 16):
“Our unbiased single-cell RNA-seq data using the immune cells of both mouse models revealed that the intratumoral lymphocytes and macrophages were dramatically remodeled by anti-CD47 treatment. Single-cell RNA-seq provides a unique advantage compared to the unsupervised analysis of cell subpopulations, with an ability to analyze thousands of genes on an individual cell [44, 45]. Our study demonstrated that anti-CD47 treatment led to changes in the tumor microenvironment with increased pro-inflammatory macrophages that exhibit anti-tumor effect, while reduced anti-inflammatory macrophages that are associated with immunosuppression. Moreover, anti-CD47 treatment increased the proportions and numbers of intratumoral lymphoid cells.”
Pan (p. 2) also states:
“We investigated the effect of anti-CD47 in patient-derived PDAC xenografts and studied the mechanism of such effect using single-cell RNA-sequencing (scRNA-seq), a high dimensional profiling to evaluate functional and genetic changes of tumor-infiltrating immune cell populations of syngeneic mouse models following CD47 targeting.”
Note that single-cell RNAseq determines the expression level of all transcriptionally active genes in the cell. Thereby, the method of Pan necessarily determines the expression level of each of the a NKG7, GNLY, FGFBP2, GZMH, CTSW, CCL5, CD8A, KLRD1, PRDM1, ZEB2, S100A8, S100A9, S100A12, LYZ, LST1, FCN1, TYROBP, FCER1G, AIF, CTSS, CYBB, SPI1, HLA-DRA, STAT1, IFITM2, and LY6E genes in the T-cells.
The presently claimed method differs from the method of Pan in that Pan does not teach the limitation of “receiving a single cell RNA sequencing dataset for T-cells from the subject.” Rather, Pan teaches performing single-cell RNA sequencing (scRNA-seq).
However, after generating the RNA sequencing dataset for the T-cells, the RNA sequencing dataset is necessarily provided to and thereby received by someone or by a computer to permit the practioner to compare the RNA sequencing dataset for the T-cells to a control dataset. Accordingly, the receiving step would have been an obvious addition to the method of Pan as part of a conventional workflow process. Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Pan so as to have received the RNA sequencing dataset for the T-cells of the subject from a different laboratory or entity. One would have been motivated to have done so in those instances in which different laboratories or entities performed the step of scRNA-seq of the T-cells and the step of comparing and analyzing the scRNA-seq dataset using a random forest model.
Further, the presently claimed method differs from the method of Pan in that Pan does not teach that the comparing step is accomplished using a Random forest model. Rather, Pan teaches that the comparing the expression levels of the dataset to control expression levels is accomplished using the Seurat pipeline (e.g., p. 4 “Data preprocessing with Seurat package” and “Cluster specific gene identification and marker-based classification”).
However, Pouyan teaches methods of using a random forest model to analyze datasets obtained by single cell RNA sequencing (scRNA-seq; e.g., abstract and section “3.1 beginning at p. 182, col. 1).
Pan (abstract) states:
“Here, we present RAFSIL, a random forest based approach to learn cell–cell similarities from scRNA-seq data. RAFSIL implements a two-step procedure, where feature construction geared towards scRNA-seq data is followed by similarity learning. It is designed to be adaptable and expandable, and RAFSIL similarities can be used for typical exploratory data analysis tasks like dimension reduction, visualization and clustering. We show that our approach compares favorably with current methods across a diverse collection of datasets, and that it can be used to detect and highlight unwanted technical variation in scRNA-seq datasets in situations where other methods
fail.”
It is also stated at p. i80, col. 1:
“our approach requires no prior information about group structure. We show RAFSIL learns similarities that faithfully represent group structure in scRNA-seq data; when used for dimension reduction and clustering they provide an accurate visualization of datasets and enable exploratory analyses for cell type identification and discovery. Importantly, RAFSIL compares favorably with the current state-of-the-art showing high accuracy and robustness, and we demonstrate how it enables the identification of
technical variation that remains hidden with other approaches.”
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Pan so as to have compared the scRNA-seq dataset for the T-cells from subjects to control RNA expression levels using the random forest model of Pouyan. One would have been motivated to have done so because Pouyan teaches that this is an effective means for comparing and analyzing scRNA-seq data and provides the advantages of the advantages of avoiding unwanted technical variation in scRNA-seq datasets while provide an accurate visualization of datasets of the identification of cell types.
Regarding the final step of the claims of “thereby classifying the individual T-cells as infection microenvironment reactive or tumor microenvironment reactive,” since the modified method of Pan includes the same steps as that of present claim 14, the method necessarily has the same result of “thereby classifying the individual T-cells as infection microenvironment reactive or tumor microenvironment reactive.”
Regarding the preamble of the claims, by analyzing and classifying the T-cells present at the tumor, the method of Griffiths necessarily is one for determining a T-cell “microenvironment reaction.” Additionally, the preamble of the claim is not in agreement with or of the same scope as the final step of the claims. As set forth in MPEP 2111.02 II: “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention' s limitations, then the preamble is not considered a limitation and is of no significance to claim construction.” Herein, the preamble language is a statement of purpose and intended result and does not result in a manipulative difference in the method steps of the claims. Accordingly, the process steps are able to stand alone and the preamble limitation is not considered to materially distinguish the claimed method over the prior art.
Regarding claim 57, Pan teaches that the cancer subject is a subject having pancreatic cancer (e.g., “Patients and tissue samples” at p. 2).
Regarding claim 58, in the method of Pan, the T-cells are tumor-infiltrating T-cells (e.g., p. 8).
Regarding claim 59, this claim recites treating the subject only if the T-cells from the subject are classified as tumor microenvironment reactive. Claim 59 includes the embodiment of not treating the subject if the T-cells from the subject are not classified as tumor microenvironment reactive. Pan teaches a method that does not classify the T-cells from the subject as tumor microenvironment reactive and which does not further treat the subject and thereby meets the limitations of claim 59.
Regarding claim 60, in the method of Pan, the control is an expression level of the genes in subjects known not to have cancer or the control is an expression level of the genes in subjects known to have cancer (e.g., p. 8, col. 1 “Composition of tumor-infiltrating immune cell subpopulations identified by single-cell RNA-seq”).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CARLA J MYERS whose telephone number is (571)272-0747. The examiner can normally be reached M-Th 6:30-5:00 EST.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682
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