DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on December 23, 2025 has been entered.
Action Summary and Claim Status
This action is in response to the papers filed on December 23, 2025.
Currently claims 1-7 and 9-23 are pending.
Claim 8 was canceled by applicant.
Claims 10 and 12-21 were withdrawn as directed to a non-elected invention/species.
New claims 22-23 were added in the response filed on June 11, 2025.
Claims 1-7, 9, 11, and 22-23 are under examination.
Any objections and rejections not reiterated below are hereby withdrawn.
Priority
This application, filed on January 18, 2022, is a 371 of PCT/JP2020/027649, filed on July 16, 2020 and claims priority to the foreign application JAPAN 2019-134181, filed on July 19, 2019.
It is noted that no translation of the foreign application has been provided. Therefore, the effective filing date of the application is determined to be July 16, 2020 (the filing date of the PCT application).
Specification
The disclosure is objected to because of the following informalities:
Replacement tables 1B on page 7 and 2B on page 14 are partially obscured by a textbox with non-English language characters (See below).
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Appropriate correction is required.
Claim Rejections - 35 USC § 112(a) – New Matter
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.
Claim 1 is rejected under 35 U.S.C. 112(a) 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, at the time the application was filed, had possession of the claimed invention.
This is a NEW MATTER rejection.
As presently amended, claim 1 recites the following newly added claim terms:
“a computer executing a classification program”
“a clustering algorithm that classifies the test sample by comparing the gene expression profile with reference expression profiles of known subtypes”
“a scoring algorithm that calculates a differentiation score based on relative expression levels among gene groups”
These terms do not appear in the specification as originally filed. The remarks filed with the new claims dated December 23, 2025 assert that support for the amendments to the claims: “can be found in Example 4 of the specification which states that “cluster analysis was performed by the group-average method based on Euclidian distance using Expression View Pro software (MicroDiagnostic).” It is also supported by Example 5, which describes ROC analysis and … the regression coefficients calculated by multiple logistic regression analysis…” Since ROC analysis and multiple logistic regression analysis are generally performed using software programs, these examples disclose the use of a computer program for carrying out the calculations.”
The assertion that a particular set of calculations are “generally performed using software programs” does not describe a particular computer required to perform the claimed method. Furthermore, no particular “clustering algorithm” or “scoring algorithm” is described in the specification.
Applicant is required to cancel the new matter in the reply to this Office Action.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 recites the phrase: “…the differentiation marker gene set including a combination of genes obtained by selecting…”. It appears that this phrase is missing a suitable transitional phrase and a helping verb. It is suggested that this phrase could be revised to: “wherein the differentiation marker gene set including a combination of genes is obtained by selecting…”
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a) - Enablement
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.
Claims 1-7, 9, 11, and 22-23 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for differentiating or classifying breast cancer based on the expression levels of: a) the combination of 15 genes demonstrated in Example 7 and b) the combination of CLCA2, GRB7, and ORMDL2 (ORMDL3?) for differentiating HER2 positive-like breast cancer from other subtypes demonstrated in the new example included in the remarks filed on June 11, 2025, does not reasonably provide enablement for differentiating or classifying breast cancer based on the expression of “at least one gene from each gene group of at least one gene group” (i.e. “at least one gene”). 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.
This rejection is maintained in view of the indefinite scope of the claims with respect to the requirement that the differentiation marker gene set comprises at least one gene from each gene group among groups a to o, recited by claim 1. As is discussed in the 112(b) and 112(d) rejections below, dependent claims 7, 9, and 11 recite “genes included in each gene group selected in accordance with the desired subtype…” (claim 7), “wherein the at least one gene group selected in accordance with the desired subtype…” (claim 9), “all genes included in each gene group of a plurality of the gene groups thus selected” (claim 11). Therefore, it appears that while claim 1 has been narrowed to the scope previously determined to be enabled in the rejections of record (i.e. measuring at least one gene from each of the gene groups a through o, or the combination of CLCA2, GRB7, and ORMDL2 (ORMDL3?) for differentiating HER2 positive-like breast cancer from other subtypes demonstrated in the new example included in the remarks filed on June 11, 2025), dependent claims 7, 9, and 11 recite broader claim language not requiring all of the 15 gene groups required by amended claim 1.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404, “Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of 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.”
The nature of the invention and the breadth of the claims
Claims 1 and 23 are broadly drawn to a method of differentiating or classifying a subtype of breast cancer in a test sample comprising a step of measuring expression levels of genes included in a differentiation marker gene set, and a step of differentiating or classifying whether the test sample is a particular subtype of breast cancer. Claim 1 requires that the differentiation gene set includes a combination of genes obtained by selecting at “least one gene from each gene group of at least one gene group”. Therefore, the broadest reasonable interpretation of the claims is: measuring an expression level of at least one gene from at least one of the recited gene groups in a breast cancer test sample and differentiating or classifying whether the test sample is a particular subtype of breast cancer.
Claims 2-7 further require that the differentiating or classifying step comprises comparing the expression levels of the measured gene(s) to those measured in a sample from a breast cancer patient having the cancer subtype in question (i.e. a positive control).
The elected embodiment within the scope of claim 9 requires measuring expression levels of a combination of at least 3 genes (at least one gene from group i, group j, and group k) for the desired subtype HER2 positive-like.
Other embodiments not elected within the scope of claim 9 include, for example, embodiments (vii) for phyllodes tumor and (viii) squamous cell carcinoma requiring measuring expression level(s) of at least one gene selected from only one group of genes (i.e. encompassing measuring a single gene).
Claim 11 requires measuring expression levels of all of the genes in groups i, j, and k.
Claim 22 further requires a step of collecting the test sample from the subject. Claim 23 further requires administering a treatment to the subject.
The state of the art
The invention is in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The prior art teaches differentiating or classifying subtypes of breast cancer comprises several qualities that distinguish different cancers. For example, Hennigs et al., BMC Cancer 16:734 “Prognosis of breast cancer molecular subtypes in routine clinical care: A large prospective cohort study” (2016) teaches five molecular “intrinsic subtypes” of breast cancer are well recognized in the art (Hennigs, page 2, column 2, paragraph 1), namely: Luminal A-like, Luminal B/HER2 negative-like, Luminal B/HER2 positive-like, HER2-type, and Triple Negative. Hennigs teaches that HER2 positive-like tumors are ER and/or PR (-), HER2 (+), and Ki-67 (+) or Ki-67 (-), in contrast to the applicant’s special definition. (Hennigs, page 2, column 2, Subgroups table) Hennigs further teaches that tumors can be classified into intrinsic subtypes based on the World Health Organization standards comprising: grading on along Elston and Ellis scale, grouping into stages according to the TNM classification, and measurement of expression of the following genes: estrogen receptor(ER) , progesterone receptor(PR), HER2(ERBB2), and Ki-67, as assessed with an immunohistochemistry (IHC) assay (i.e. gene expression measurement based on the amount of protein) (Hennigs, page 2, column 1, paragraph 6- column 2, paragraph 3) Hennigs further teaches differentiating subtypes as “carcinoma-in-situ” or “invasive cancer”. (Hennigs, Table 3) Furthermore, Hennigs teaches that about 4% of invasive cancers failed distinct subtype distribution based on the combination of factors including measurement of expression of ER, PR, HER2, and Ki-67. (Hennigs, table 3)
Sorlie et al. “Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications” PNAS Vol. 98, No. 19, 10869-10874 September 11, 2001) teaches distinguishing breast cancer subclasses by measuring gene expression using a microarray (i.e. gene expression measurement based on the amount of RNA), (Sorlie, abstract) comprising measuring the abundance of RNA molecules corresponding to 8,102 genes. (Sorlie, page 2, column 1, paragraph 2) Sorlie further teaches clustering (i.e. classifying) tumors into subclasses comprising the 5 intrinsic subtypes based on the expression levels of 427 unique genes selected from the 8,102 gene set. (Sorlie, Figure 1) Sorlie teaches that breast tumors are heterogenous with respect to gene expression, and that observation of multiple genetic alterations is important for differentiation between subtypes. (page 1, column 1, paragraph 2) Further, Sorlie teaches that gene expression levels are highly diverse within subtypes, and that in particular, ER+ tumors may be further subclassified into groups with differences in 5-year patient outcomes. (Sorlie, page 6)
Guidance in the specification and working examples
The specification teaches a method for differentiating and classifying breast cancer by subtypes, wherein the subtype may be luminal A, luminal B (HER2 positive), luminal B (HER2 negative), HER2 positive, HER2 positive-like, triple negative, phyllodes tumor, squamous cell carcinoma, normal-like, normal and undeterminable (paragraph 0013). The specification defines: “Undeterminable refers to a case in which the gene expression profile is not similar to any of those of luminal A, luminal B (HER2 positive), luminal B (HER2 negative), HER2 positive, HER2 positive-like, triple negative, normal-like, normal, squamous cell carcinoma, and phyllodes tumor.” (paragraph 0015) Furthermore, the specification distinguishes between “normal” and “normal-like”: “normal refers to normal tissue” and “normal-like refers to a case that is clinicopathologically diagnosed as cancer, but has a gene expression profile similar to that of normal mammary gland tissue.”
The specification teaches “as the number of genes for which the expression levels are measured increases, the accuracy of subtype differentiation or classification improves”. (paragraph 0023)
Figure 3 “shows a heat map of results of cluster analysis… for 470 cases by using a differentiation marker gene set of 15 kinds of genes indicated in Example 7” (paragraph 0012) In example 7, expression of 15 genes (one from each group) were measured, including CLCA2 from group i, GRB7 from group j, and ORMDL3 from group k. (paragraph 0066). The expression ratio for each of these genes (or the combination of all 3) does not appear to differ significantly between cases assigned to the “HER2 positive-like” cluster and many cases assigned to the “Luminal A” or “TNBC” clusters (Figure 3). Furthermore, it appears that expression of these 3 representative genes varies widely within each of the clusters of cases. For example, some cases assigned to “Luminal A” have very high expression of the group i, j, and k representative genes, while others have low to moderate expression ratios of these genes. (Figure 3)
The specification does not provide a working example that only analyzes 3 genes, one each from groups i, j, and k, as elected by Applicants. However, in the response filed on June 11, 2025, Applicant provided a new “follow-up analysis” asserted to have been “performed using data already obtained at the time of filing and disclosed in the specification, and that the analysis was conducted under the same conditions as those described in the specification” (“Response to Office action dated Mar 11, 2025”, filed June 11, 2025, page 20 of 22). The new analysis provides a working example of discrimination between HER2 positive-like breast cancer and other subtypes using gene expression data for “CLCA2, GRB7, and ORMDL2”. It is noted that while “CLCA2” and “GRB7” are present in the original specification and claims as belonging to groups “i” and “j”, respectively, group “k” comprises “ORMDL3”. “ORMDL2”, cited by the new analysis, is not present in the claims, and does not appear within the specification as originally filed. It is unclear whether the new analysis was done with “ORMDL3” or “ORMDL2”. In the interest of compact prosecution, this scope of enablement analysis and rejection assumes that applicant intended to cite and actually analyzed the originally supported gene “ORMDL3” in the response, rather than the unsupported NEW MATTER “ORMDL2”.
The specification as originally filed does not teach any working examples of classifying or differentiating breast cancer subtypes comprising measuring fewer than a combination of 15 genes.
Quantity of experimentation
Claim 1 is broadly drawn to a method of differentiating or classifying breast cancers by subtype based on measurement of gene expression of at least one gene from at least one of the recited gene groups (a to o). (i.e. at least one gene). The specification teaches subtypes encompasses: luminal A, luminal B (HER2 positive), luminal B (HER2 negative), HER2 positive, HER2 positive-like, triple negative, phyllodes tumor, squamous cell carcinoma, normal-like, normal and undeterminable (paragraph 0013) , or alternatively, “Luminal A+B” (paragraph 0015)
The specification teaches analysis of expression levels for 15 genes, wherein one gene is measured from each of the 15 gene groups (i.e. 15 genes in total), and the resulting 15 “differentiation scores” were used to cluster the cases into subtypes. The specification teaches an “undeterminable” cluster of tumors that cannot be classified by the combination of all of the genes recited in the claims (page 57, paragraph 4), but does not teach the number of tumors assayed that were assigned to this group.
The prior art teaches breast cancer subtypes encompasses: Luminal A-like, Luminal B/HER2 negative-like, Luminal B/HER2 positive-like, HER2-type, and Triple Negative (Hennigs, page 2, column 2, Subgroups table), and that about 4% of invasive cancers failed distinct subtype distribution based on the combination of factors including measurement of expression of ER, PR, HER2, and Ki-67. (i.e. measurement of expression of four genes) (Hennigs, table 3) Furthermore, Sorlie teaches that individual breast cancer tumors are highly heterogenous with respect to gene expression and genetic variation (Sorlie, page 1, column 1, paragraph 2), expression levels of any given gene of a 427 gene panel are highly variable within recognized breast cancer subtypes, and that recognized subtypes (for example, ER+) can be further subdivided based on expression of hundreds of genes into groups with different clinical outcomes. (Sorlie, page 6)
Therefore, it is unpredictable that the skilled artisan could accurately differentiate or classify breast cancer tumors into any subtype based on the expression level of at least one gene from at least one of groups i, j, and k, as broadly claimed. The instant specification teaches that accuracy of subtyping increases with increasing numbers of measured genes, and that a group of tumors remain “undeterminable” even when measuring expression of hundreds of genes simultaneously. The prior art teaches that measurement of expression of single genes (i.e. ER) or small groups of genes (i.e. ER, PR, HER2, and Ki-67), do not allow for unequivocal assignment of breast cancer tumors to defined subtypes. The skilled artisan would be required to perform additional undue experimentation to determine whether the claimed measurement of any one, or any small group, of the recited genes other than the specific combination “CLCA2, GRB7, and ORMDL2 (ORMDL3?)” within the elected species “at least one gene from each gene group of”… “the group i… and the group j, and the group k” for HER2 positive-like breast cancer provided in the new working example, would differentiate or classify breast cancers into the recited subtypes.
The quantity of experimentation in this area is large, since there is evidence in the specification and prior art that many breast cancers are not assignable to the recited subtypes based on clustering on gene expression patterns for hundreds of genes. Furthermore, there is no guidance in the specification or art or new working example that supports measurement of expression of a single gene that is adequately diagnostic of breast cancer subtype.
Level of skill in the art
The level of skill in the art is deemed to be high.
Conclusion
In the instant case, given the breadth of the claim to classifying or differentiating any breast cancer based on the expression level of at least one gene, the lack of guidance provided in the specification and prior art as to how to reliably differentiate between breast cancers by measuring expression of single (or small groups of) genes, the large quantity of undue experimentation required, lack of demonstrated working examples comprising measuring expression of one of the recited genes from one of the recited gene groups, and the unpredictability of the art, balanced only against the high level of skill in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the method of claims 1-7, 9, 11, and 22-23 as broadly recited in the present claims.
Response to Arguments
The response traverses the enablement rejection of claims 1-7, 9 and 11 under U.S.C. 112(a). In the response, a new exemplary clustering analysis of gene expression levels in breast cancer and control samples using the same data and methodology disclosed by the specification is provided. This example analysis provides evidence that the combination of CLCA2, GRB7, and ORMDL2 allows for classification of a high proportion of HER2-positive like cases into a single cluster. The response argues that, given this working example, it would be readily apparent to those skilled in the art that similar discrimination is possible using other combinations of genes from the i, j, and k groups, and that the same approach can be applied to other subtypes as well.
This argument has been thoroughly reviewed and is not found to be persuasive. The evidence provided by the new analysis provides support for the single narrow embodiment within claim 9 (see claim 9 (v)) wherein CLCA2 is selected from group (i), GRB7 is selected from group (j), and “ORMDL2” is selected from group (k) to differentiate HER2 positive-like cancers from other subtypes (including the recited “undeterminable” subtype). As has been described in the maintained and updated 112(a) scope of enablement rejection above, the broadest reasonable interpretation of claim 1 encompasses a method comprising measuring only one gene (“at least one gene from each gene group of at least one gene group…”). Furthermore, the non-elected embodiments of claim 9 directed to other combinations of genes selected from other groups of genes for differentiation of other subtypes clearly encompass embodiments wherein only a single gene is measured (e.g. “[the at least one gene group is selected from]… the group “a” for calculating a squamous cell score…”) Therefore, while the new example documented in Applicants’ arguments filed on 06/11/2025 could potentially provide additional support over the originally filed specification for the single exemplary embodiment within the elected species recited by claim 9 (v), it does not reasonably enable the broadest reasonable interpretation of the claims (i.e. differentiating or classifying based on the expression level of a single gene) as presently written. Furthermore, it is noted that the new example demonstrating CLCA2, GRB7, AND ORMDL2 expression patterns cites “ORMDL2” expression, while the claims recite measuring “ORMDL3” expression. ORMDL2 is not present in the specification, however only ORMDL2 and not ORMDL3 is referenced in the remarks comprising the new example. It is unclear if this is a typographical error present throughout the remarks, or if this represents an intentional departure from the matter disclosed in the specification and claims.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
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.
Claims 1-7, 9, 11, and 22-23 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1 and 23 recite “a subtype of breast cancer” “selected from a group composed of…normal…”. The specification states “normal refers to normal tissue” (page 18) (i.e. not breast cancer). It is unclear how “a subtype of breast cancer” is meant to encompass tissues that are not breast cancer.
Claims 1 and 23 contain replacement table 1B and 2B, respectively, that are partially obscured by a text box containing non-English language characters. Therefore, it is unclear whether the genes “CCNB2” and “ANLN”, recited by the previous version(s) of the claims, have been replaced in the amended tables 1B and 2B.
The terms “…when having an expression profile equivalent to the expression profile…” and “…having an expression profile of genes different from the expression profile…” in claim 3 are relative terms which render the claim indefinite. The terms “equivalent” and “different” are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification defines “Here, “have equivalent gene expression profiles” means that the expression profiles of each gene included in the gene set for differentiating or classifying the subtype of breast cancer are similar. Further, “have different gene expression profiles” means that the expression profiles of each gene included in the gene set for differentiating or classifying the subtype of breast cancer are not similar.” (paragraph 0041). The specification does not provide any guidance as to the metes and bounds of the terms “similar” or “not similar”. It is not clear whether a “similar expression level” of a given gene must be: equal to a reference value, vary from a reference value by less than some percentage of the reference value, be closer to one reference value (e.g. for a subtype “a”) than another reference value (e.g. subtype “b”), or whether some other criteria/standard is to be applied to the comparison(s).
Claim 7 recites the limitation "determined on the basis of the expression levels of genes included in each gene group selected in accordance with the desired subtype to be differentiated, or an average value thereof". There is insufficient antecedent basis for this limitation in the claim. Claims 1, 2, and 6, upon which claim 7 depends, do not recite a step of “selecting gene groups in accordance with a desired subtype…”
Claim 7 is indefinite because it does not end in a period. As provided in MPEP 608, each claim begins with a capital letter and ends with a period.
Claim 9 recites the limitation “the at least one gene group selected in accordance with the desired subtype…”. There is insufficient antecedent basis for this limitation in the claims. Furthermore, this is a broader recitation of the “selecting at least one gene from each gene group among groups a to o…” recited by claim 1.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Therefore, it is unclear whether claim 9 requires a combination of 15 genes (one from each gene group), or only requires at least one gene selected from at least one gene group.
Claim 9 further recites several combinations comprising fewer than the combination of 15 gene groups recited by claim 1. It is likewise unclear how these broader claim terms are meant to be encompassed within the narrower recitation in claim 1 requiring at least one gene from each of the 15 gene groups a to o.
Claim 11 recites the limitation “all genes included in each gene group of a plurality of the gene groups thus selected”. There is insufficient antecedent basis for this limitation in the claims. Furthermore, this is a broader recitation of the “selecting at least one gene from each gene group among groups a to o…” recited by claim 1.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Therefore, it is unclear whether claim 11 requires all of the genes recited by each of the gene groups (i.e. includes/comprises all 199 genes recited by tables 1A and 1B) or only requires all of the genes selected from at least one gene group (e.g. m group, comprising one gene, ESR1).
Claims 2-7, 9, 11, and 22-23 are also indefinite because they necessarily include the indefinite limitations of the claims upon which they depend.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 7, 9, and 11 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to include all the limitations of the claim upon which it depends.
Claim 1 requires “…the differentiation marker gene set including a combination of genes obtained by selecting at least one gene from each gene group among groups a to o…” (i.e. claim 1 requires a combination of marker genes comprising at least one gene from each of the recited 15 gene groups; at least 15 genes).
Claim 7 recites “each gene group selected in accordance with the desired subtype…”.
It is unclear whether this claim language requires measuring an expression level of “at least one gene from each gene group among gene groups a to o”, as recited by claim 1, or is a broader recitation requiring a gene set comprising at least one gene group from a smaller subset of gene groups selected from groups a to o.
Claim 9 recites “the at least one gene group selected in accordance with the desired subtype…” and combinations (“i” through “viii”, “x” and “xi”) explicitly requiring fewer than all 15 gene groups recited by claim 1.
Therefore, claim 9 does not presently require “selecting at least one gene from each gene group among groups a to o”.
Applicant may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims comply with the statutory requirements.
Claim Interpretation
Applicant has provided a special definition for the claim term “HER2 positive-like”: “The term "HER2 positive-like" refers to a case in which HER2 is negative, but other gene expression profiles are similar to most of the cases clinicopathologically diagnosed as HER2 positive.” (pg 14, para. 6)
Claim Rejections - 35 USC § 101
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 1-7, 9, 11, and 22-23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, ““[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106,
part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility.
Question 1
The claimed invention is directed to a process that involves a natural principle and a judicial exception.
Question 2A Prong I
The claims are taken to be directed to a natural phenomenon and abstract ideas.
Claims 1 and 23 are directed to “a method of differentiating or classifying a subtype of breast cancer in a test sample… comprising a step of measuring, in the test sample, expression levels of genes… using a primer or a probe for the genes or labels thereof and a step of differentiating or classifying whether the test sample is a desired subtype…by a computer executing a classification program… only based on the expression levels… wherein the classification program… classifies… by comparing … with a reference… or calculates a differentiation score based on relative expression…” Claim 2 requires acquiring an expression profile (i.e. analyzing the data) from the genes measured and comparing the expression profile with that of a sample from a breast cancer patient known to have the subtype in question (i.e. comparison to a positive control). Claim 3 requires evaluating whether the test sample is breast cancer of the subtype in question based on whether the test sample expression profile is “equivalent” to that of the positive control. Claims 4-5 require that the comparison is performed by “cluster analysis” or by comparing to a predetermined threshold value. Claims 6-7 require “calculating a subtype differentiation score” based on the expression levels of measured genes.
Claims 1 and 23 are directed to a process that involves the judicial exception of a law of nature/natural phenomenon (i.e. the natural correlation between expression levels of genes in a test sample and differentiation or classifying a subtype of breast cancer from which the sample was isolated), an abstract idea (a mental step) (i.e. differentiating or classifying, comparing, evaluating and calculating), and an abstract idea (i.e. a comparison to control). The step of “acquiring an expression profile… from the expression levels of the genes thus measured” required by claim 2 is likewise an abstract idea (data analysis, a mental step).
Claims 1-7, 9, 11, and 23 each recites a correlation between expression levels and differentiating or classifying a subtype of breast cancer. A correlation that preexists in the human is an unpatentable phenomenon. The association between the expression levels of groups of genes in a breast cancer test sample and the subtype identity of said breast cancer is a law of nature/natural phenomenon.
The claims also encompass abstract ideas and mental processes. Claim 1 further requires a step of differentiating or classifying whether the test sample is a desired subtype based on the natural correlation of gene expression levels and subtypes of breast cancer. Differentiating and classifying are each mental steps that could be performed by a human using mental steps or basic critical thinking which are abstract ideas. The “differentiating or classifying” steps, recited by claims 1-7, 9 and 11 amount to no more than an “instruction to apply the natural law” through mental steps. Even if the step requires something more, such as to verbalize the discovery of the natural law, this mere verbalization is not an application of the natural law to a new and useful end. These steps fail to provide the “practical assurance” sought by the Prometheus Court that the “process is more than a drafting effort designed to monopolize the law of nature itself.”
Claims 1-7 require comparing the expression profile in a test sample and an expression profile of a corresponding differentiation marker in a “sample derived from a breast cancer patient having the desired subtype to be differentiated or classified” (i.e. a positive control). A comparison to control is an abstract idea. (See MPEP 2016.04(a)(2)(III)(A); claims to “comparing BRCA sequences and determining the existence of alterations,” where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014)
Claims 2-7 and 9 require acquiring an expression profile. Acquiring an expression profile encompasses acquiring data from a database of gene expression data, or measuring absolute or relative amount(s) of mRNA(s) or protein(s) in a test sample. This is an abstract idea because the acquiring data may be performed mentally by looking at data from a database.
Claims 6-7 are directed to calculating steps comprising comparing the expression levels of genes in the groups measured (or average values thereof) to each other for each of the samples to be differentiated or classified. (i.e. comparing the expression level of a gene or genes in group i to those in group j and group k) This is an abstract idea because the calculation steps may be performed mentally.
Question 2A Prong II
The exception is not integrated into a practical application of the exception. The claims do not recite any additional elements that integrate the exception into a practical application of the exception. While the claims recite “measuring, in the test sample, expression levels of genes”, this is not an integration of the exception into a practical application. Amended claim 1 recites “using a primer or a probe for the genes or markers thereof” and new claim 22 recites “collecting the test sample from a subject”. These limitations are not integrations of the exception into a practical application. Instead, these elements reciting generic data gathering steps amount to insignificant presolution activity required to perform the method of differentiating or classifying breast cancer.
Claim 1, as amended in the response dated December 23, 2025, now recites “a computer executing a classification program… includ[ing] at least one of: a clustering algorithm that classifies the test sample by comparing the gene expression profile with reference expression profiles of known subtypes; or a scoring algorithm that calculates a differentiation score based on relative expression levels among gene groups”.
This requirement that the step of differentiating or classifying is carried out by a computer executing a classification program does not integrate the judicial exception(s) into a practical application. The recitation of “a computer executing a classification program” does not require any particular computer or particular classification program in addition to the previously recited abstract comparisons to control samples. Therefore, this recitation amounts to no more than an instruction to apply the abstract idea(s) on a generic computer.
The recitation of “a computer executing a classification program” fails to recite details of how a solution to a problem is accomplished. The requirement that the classification program includes at least one of: i) a clustering algorithm that classifies the test sample by comparing the gene expression profile with reference expression profiles or ii) a scoring algorithm that calculates a differentiation score based on relative expression levels among gene groups”. The functional language recited by i) and ii) do not meaningfully limit “a classification program”. See MPEP 2106.05(f): “The recitation of claim limitations that attempt to cover any solution to an identified problem with no restriction on how the result is accomplished and no description of the mechanism for accomplishing the result, does not integrate a judicial exception into a practical application or provide significantly more because this type of recitation is equivalent to the words "apply it". See Electric Power Group, LLC v. Alstom, S.A., 830 F.3d 1350, 1356, 119 USPQ2d 1739, 1743-44 (Fed. Cir. 2016); Intellectual Ventures I v. Symantec, 838 F.3d 1307, 1327, 120 USPQ2d 1353, 1366 (Fed. Cir. 2016); Internet Patents Corp. v. Active Network, Inc., 790 F.3d 1343, 1348, 115 USPQ2d 1414, 1417 (Fed. Cir. 2015).”
Furthermore, the claim language invokes computers merely as a tool to perform an existing process. As is clear from the specification, “For cluster analysis, known software can be used and, for example, while not limited to the following, Expression View Pro software… can be used as commercially available software.” (Specification, paragraph 0042). See MPEP 2106.05(f): “Use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application or provide significantly more. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016)”
New claim 23 differs from claim 1 in scope only in that it further requires a step of administering “an effective amount of an anticancer drug effective against a specific subtype of breast cancer” to the subject. This step appears to be described in the specification only at paragraph 0053: “Anticancer drugs (for example, paclitaxel, cisplatin, carboplatin, or docetaxel) and combinations thereof, administration methods, dosages, and the like effective for breast cancer belonging to each subtype are known, and those skilled in the art can implement chemotherapy in accordance with the histological type, as appropriate.” Therefore, the recited “treatment step” does not integrate the judicial exception into a practical application of the judicial exception because it does not recite any particular treatment to a disease or medical condition. Rather, the generically claimed (and described) treatment step amounts to an instruction to the skilled artisan to apply any known (or as yet unknown) effective anticancer drug to the cancer classified by use of the judicial exception.
Accordingly, the claims are directed to judicial exceptions.
Question 2B
The second step of Alice involves determining whether the remaining elements, either in isolation or combination with the other non-patent eligible elements, are sufficient to “transform the nature of the claims into a patent-eligible application” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
The claims are not sufficiently defined to provide a method which is significantly more than a statement of a natural principle for at least these reasons:
The claims do not add a specific limitation other than what is well-understood, routine, and conventional in the field. Steps directed to measuring expression levels of genes in a test sample are mere data gathering steps that amount to extra solution activity to the judicial exception. The measuring step tells users to measure expression levels of genes using any primer or probe for the genes or markers thereof. These measuring steps are recited at a high level of generality. Measuring the expression levels of genes in breast cancer samples was well known in the art at the time the invention was made. The prior art, for example, Kabos, teaches measuring expression levels of genes in breast cancer samples by hybridizing purified RNA to the Affymetrix Human Gene 1.1 ST Array comprising probes for each of the genes recited in the claimed invention (gene groups i, j, and k). (Kabos, page 417, column 2, paragraph 4 – page 418, column 1, paragraph 1 “Gene Expression Profiling”) The claims do not require the use of any particular non-conventional reagents. Additionally, the specification teaches “measurement methods of a transcription product of a gene are known…typical measurement methods [are] described…the present invention is not limited to these methods, and a known measurement method can be used” (Specification 0034) The specification further teaches a number of measurement methods suitable for measuring gene expression levels, and that “any of these is a known method and described in appropriate protocol in the art”. (Specification, 0035-0038) Similarly, the requirement of claim 22 to further collect the test sample from a subject does not require the use of any particular non-conventional reagents or method steps. The newly added recitation in claim 1 that the step of differentiating or classifying is carried out by a computer executing a classification program wherein the classification program includes at least one of a clustering algorithm that classifies the sample by comparing the gene expression profile to a control or a scoring algorithm that calculates a differentiation score based on relative expression levels among gene groups is well-understood, routine and conventional in the prior art. As is clear from the specification, “For cluster analysis, known software can be used and, for example, while not limited to the following, Expression View Pro software… can be used as commercially available software.” (Specification, paragraph 0042).
Finally, the recited treatment step required by claim 23 explicitly requires only applying well-known, routine, and conventional treatments known to those skilled in the art (specification, paragraph 0053).
When recited at this high level of generality, there is no meaningful limitation that distinguishes this step from well understood, routine, and conventional activities prior to applicant’s invention and at the time the application was filed.
For these reasons, the claims are rejected under section 101 as being directed to non-statutory subject matter.
Response to arguments
The response traverses the rejection of claims 1-7, 9, 11, and 22-23 under U.S.C. 101 as being directed to non-statutory subject matter on the grounds that the response asserts that the newly added recitation of a computer executing a classification program… must be performed only by the computer and cannot be carried out mentally or manually and is a practical application of underlying biological phenomena because it “transforms raw expression data into a subtype classification”.
This argument has been thoroughly reviewed and is not found to be persuasive as elaborated above in the revised 101 rejection. Briefly, the amendments to claim 1 do not integrate the judicial exceptions into a practical application, but amount to mere instructions to perform a well-known, routine and conventional classification/clustering method on a generic computer (see detailed analysis above). See also MPEP 2106.07(b), 2106(I), 2106.05(I)(A).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-4, 6, 7, 9, 11, and 22-23 remain/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kabos et al., “Patient-derived luminal breast cancer xenografts retain hormone receptor heterogeneity and help define unique estrogen-dependent gene signatures.” Breast Cancer Res Treat 135, 415–432 (2012) as evidenced by NCBI Gene Expression Omnibus Platform GPL11532 (Public on Jan 18, 2011).
It is noted that the amendment to claim 1 requiring that the step of differentiating or classifying (i.e. analyzing gene expression levels)… only based on the expression levels of the genes… does not exclude embodiments wherein other genes are measured and only at least one gene belonging to at least one of the recited gene groups is selected from the larger dataset for analysis.
It is noted that the amendment to claim 1 requiring “including a combination of genes obtained by selecting at least one gene from each gene group among groups a to o” appears to require measuring a combination of genes comprising at least 15 genes (i.e. one from each of groups a to o).
Regarding claim 1, Kabos teaches a method comprising measuring expression levels of genes in tumor specimens from breast cancer patients (i.e. a test sample) using the Affymetrix Human Gene 1.1 ST Array (i.e. using a primer or a probe for the genes or markers thereof), (Kabos, page 417, column 2, paragraph 4 – page 418, column 1, paragraph 1 “Gene Expression Profiling”) including a sample that “did not overexpress HER2 protein, [but] did express other HER2-associated genes”. (Kabos, page 420, column 1, paragraph 1) (i.e. is HER2 positive-like according to the applicant’s definition): “The term "HER2 positive-like" refers to a case in which HER2 is negative, but other gene expression profiles are similar to most of the cases clinicopathologically diagnosed as HER2 positive.” (specification pg 14, para. 6) Kabos also teaches differentiating or classifying the test samples based on the measured expression levels: “A supervised hierarchical cluster (i.e. a classification program executed by a computer comprising a clustering algorithm that classifies the test sample by comparing the gene expression profile with reference expression profiles) [based on gene expression levels] segregates the expression patterns by tumor, followed by hormone [response]” (Kabos, page 423, column 2, paragraph 2).
NCBI Gene Expression Omnibus Platform GPL11532 describes the genes measured by the “Affymetrix Human Gene 1.1 ST Array”. The following gene identifiers are present on the table of genes measured by the array: GSDMB, ORMDL3, MED24, MSL1, CASC3, WIPF2, PGAP3, STARD3, ERBB2, MIEN1, GRB7, C21orf58, ATP13A5, NUDT8, HSD17B2, ABCA12, ENPP3, WNT5A, MPP3, VPS13D, PXMP4, GGT1, TRPV6, C2orf54 (is a synonym of MAB21L4), CLDN8, LBP, SRD5A3, PAPSS2, TMEM45B, CLCA2, FASN, MPHOSPH6, NXPH4, HPGD, KYNU, GLYATL2, KMO, SRPK3, THRSP, PLA2G2A, TFAP2B, FABP7, SLPI, SERHL2, S100A9, KRT7, TMEM86A, MBOAT1). Therefore, Kabos teaches measuring all of the genes in claimed groups i, j, and k and differentiating or classifying subtypes of breast cancer.
Even more, and under further review after the December 23, 2025 amendments, it is noted that all of the 199 genes recited in tables 1A, 1B, 2A, and 2B are present on the “Affymetrix Human Gene 1.1 ST Array”. Therefore, Kabos teaches measuring the expression of all 199 of the recited genes.
Regarding claim 2, Kabos teaches comparing the expression profile of a given sample to a sample derived from a breast cancer patient having a HER2 positive-like tumor (i.e. a tumor that did not overexpress HER2 but did express other HER2-associated genes). (Kabos, page 420, column 1, paragraph 1 and Kabos, supplemental figure 5)
Regarding claim 3, Kabos teaches comparing the expression profiles of test samples to expression profiles acquired from patient samples of known subtypes (Kabos, supplemental figure 5).
Regarding claim 4, Kabos teaches comparing expression profiles among breast cancer samples by cluster analysis. (Kabos, figure 5 and supplemental figure 5)
Regarding claims 6-7, Kabos teaches calculating a subtype differentiation score from gene expression levels. (Kabos, supplemental figure 5)
Regarding claim 9, Kabos teaches measuring expression levels of at least one gene from each of the claimed gene groups i, j, and k. (for example, NXPH4, ERBB2, CASC3, respectively) (NCBI Gene Expression Omnibus Platform GPL11532).
Regarding claim 11, Kabos teaches measuring expression levels of all of the genes included in each of the claimed gene groups i, j, and k. (Kabos, as evidenced by NCBI Gene Expression Omnibus Platform GPL11532)
Regarding claim 22, Kabos teaches collecting the test samples from the subject prior to step (a) (Kabos et al., page 417, column 1, paragraph 2).
Regarding claim 23, Kabos teaches treating different subcategories of breast cancers with effective amounts of anticancer drugs effective against the subtype of breast cancer (Kabos et al., page 427-429).
Response to arguments
The response traverses the rejection of claims 1-7, 9, 11, and 22-23 as being unpatentable over Kabos et al. on the grounds that: “Kabos as evidenced by NCBI… fails to disclose or suggest the claimed differentiation marker gene set including a combination of genes selected by selecting at least one gene from each of the fifteen gene groups… [or] classification of a test sample into eleven distinct breast-cancer subtypes.
This argument has been reviewed and is not found to be persuasive. It is noted that the amended claim language does not exclude embodiments wherein other genes are measured in addition to those recited by the claims and an analysis (i.e. a classification) is made based on the expression levels of the recited genes extracted from a larger dataset. Recitations of “a gene set including a combination of genes…” does not exclude measuring additional genes in addition to the genes recited by the claims (i.e. is open-ended claim language equivalent to “a gene set comprising…”). Therefore, this argument is not commensurate in scope with the claims as presently written.
As described in the 102 rejection above, Kabos teaches classifying a HER2-like cancer by cluster analysis (performed on a computer) comprising all of the recited genes.
The response further argues that the cited references do not teach differentiating breast cancers into the particular eleven subtypes recited by the claims. It is noted that claim 1 does not require differentiating breast cancers into each of the recited subtypes, but rather that “the subtype being selected from a group composed of…[the eleven subtypes]” (i.e. any one of the recited eleven subtypes). Therefore, this argument is likewise not commensurate in scope with the claims as presently written.
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.
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 5 is rejected under 35 U.S.C. 103 as being unpatentable over Kabos et al., “Patient-derived luminal breast cancer xenografts retain hormone receptor heterogeneity and help define unique estrogen-dependent gene signatures.” Breast Cancer Res Treat 135, 415–432 (2012) as evidenced by NCBI Gene Expression Omnibus Platform GPL11532 (Public on Jan 18, 2011) in view of Sorlie et al., “Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications” PNAS Vol. 98, No. 19, 10869-10874 September 11, 2001.
Regarding claim 5, Kabos teaches measuring the expression levels of all of the genes in claimed groups i, j, and k (Kabos, page 417, column 2, paragraph 4 – page 418, column 1, paragraph 1 “Gene Expression Profiling”) in breast cancer patient tumor samples including a HER2 positive-like patient (Kabos, page 420, column 1, paragraph 1) and classifying the tumors by clustering the samples using a computer with samples derived from patients of known tumor subtypes on the basis of gene expression profiles. (Kabos, page 423, column 2, paragraph 2 and Kabos, supplemental figure 5)
Kabos does not teach comparing the expression profiles to a threshold value.
However, Sorlie teaches a method comprising measuring gene expression profiles of breast cancer samples by microarray, clustering the tumors based on expression profiles, (Sorlie, Figure 1), calculating correlation coefficients (i.e. a subtype differentiation score), and classifying the tumors into distinct subtypes based on the relative expression of 476 genes across the samples studied. (Sorlie, Figure 2) Sorlie teaches that cluster branches with correlation coefficients <0.2 are not reflective of meaningful relationships (i.e. comparing the expression profiles with a threshold value) (Sorlie, page 10870, column 2, paragraph 4)
Sorlie further teaches that tumors belonging to the ER subtype may be subclassified into distinct subgroups based on gene expression profiles to identify expression motifs that represent clinical phenotypes like resistance to drugs, invasiveness, or metastatic potential. (Sorlie, page 10874, column 2, lines 14-22)
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to combine the method of classifying breast cancers based on gene expression profiles comprising measuring the expression of all of the claimed genes by microarray analysis, taught by Kabos, with the method of classifying breast cancers based on gene expression profiles measured by microarray analysis comprising comparing the expression profile to a threshold, as taught by Sorlie. The ordinary artisan would have been motivated to combine the method of Kabos with the method of Sorlie because of the teaching of Sorlie that classification of tumors by gene expression patterns into groups with high correlation coefficients can be used to identify biologically meaningful expression motifs that represent clinical phenotypes like drug resistance, invasiveness, or metastatic potential. (Sorlie, page 10874, column 2, lines 14-22) Therefore, the ordinary artisan would have been reasonably confident that a method of measuring expression profiles of breast cancer tumors comprising the genes taught by Kabos would have successfully subclassified tumors of unknown type into highly correlated groups with tumors of known subtypes.
Response to arguments
The response traverses the rejection of claim 5 as being unpatentable over Kabos et al. in view of Sorlie et al. on the grounds that “The secondary reference to Sorlie has been cited only for its alleged teachings against certain dependent claims… [and] fails to overcome the above-noted deficiencies of the primary reference to Kabos.”
Arguments against Kabos et al. are addressed in the 102 rejection above.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Response to Amendment
The d under 37 CFR 1.132 filed December 23, 2025 is insufficient to overcome the rejection of claims 1-7, 9, 11, and 22-23 based upon scope of enablement under 35 U.S.C. 112(a), indefiniteness under 35 U.S.C. 112(b), Kabos et al. as evidenced by NCBI under 35 U.S.C. 102, and Kabos et al. as evidenced by NCBI in view of Sorlie et al. under 35 U.S.C. 103 as set forth in the last Office action because: The evidence provided in the declaration is not commensurate in scope with the claimed invention.
The evidence provided refers to embodiments wherein gene expression of a combination of 15 genes (one gene from each of groups a to o) are analyzed “according to the same procedure described in Example 7 of the specification” compared to clustering/differentiation analyses “performed for a set of 207 genes measured in 470 specimens”.
As is described in detail in the 112(a), (b), and (d) rejections above, the recited genes (see table 1A and 1B) comprise 199 genes, are claimed using open-ended language (i.e. “gene set including…”) that does not exclude methods comprising measuring other genes in addition to those recited by the claims, and the claims as presently recited have differing scopes such that dependent claims do not require measuring gene expression of a combination comprising one gene from each of groups a to o (i.e. a combination of at least 15 genes).
Conclusion
No claim is allowed.
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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682