DETAILED ACTION
Election/Restrictions
Applicant's election with traverse of Group I, claims, 1-6 and 9, drawn to a method for diffuse large B-cell lymphoma prognosis and treatment in a patient in need thereof, in the reply filed on 12/08/2025 is acknowledged. The traversal is on the ground(s) that “the method claims 1-6, 9, 12-15, and 20-23 belong to the same Group under the PCT unity of invention Rule 13. In particular, each of independent claims 1, 12, and 20 relate to the same special technical feature, as explained in more detail below. Claims 16- 19 and 30 are withdrawn without prejudice or disclaimer.
In asserting a lack of unity of invention, the Examiner cites Alizadeh et al. as allegedly teaching the common technical feature of gene expression of LMO2 and TNFRSF9 in relation to diffuse large B-cell lymphoma. The reliance on this reference as demonstrating lack of unity of invention, merely because it discloses 2 of the recited genes, shows the error in the interpretation of the claims. Applicant notes that unity of invention was also found in the PCT stage as well as in the European examination.
Each of independent claims 1, 12, and 20 require "at least" 23 specific gene expression profiles to be determined: ALDOC, ASIP, ATP8A1, CD1E, DUSP16, FAFI,
FAM223AIFAM223B, GAREM, GNG8, LMO2, LPPR4, LY75, MAEL, PADI2, PDK1, PPP1R7, SCN1A, SLAMFI, SSTR2, TNFRSF9, USH2A, VEZF1, and WDR91.
Thus, as explained in the telephone call, this particular panel is a shared technical feature of all of the claims. Claims 2, 5, 12, and 21 further recite a second set of genes: ADRA2B, ECT2, ELOVL6, IGSF9, NEK3, PDK4, PES1, PUSL1, TADA2A, and ZMYND19, but these claims all nevertheless still require the original 23 gene panel in the method-i.e., these are detected in addition to the primary panel above.
Accordingly, each of claims 1-6, 9, 12-15, and 20-23, share the same special technical feature under PCT Rule 13. Further, they each relate to treatment methods involving this same panel, and therefore should be examined together.
Additionally, the Examiner has instituted a species election requirement requiring Applicant to choose "a specific gene or a specific combination thereof." In view of the above explanation, it is clear this species election requirement is in error because the claims are not written to permit only one specific gene. For the purposes of facilitating examination, Applicant confirms the initial species elected is the combination 23-gene panel required by each of the independent claims: ALDOC, ASIP, ATP8A1, CD1E, DUSP16, FAFI, FAM223AIFAM223B, GAREM, GNG8, LMO2, LPPR4, LY75, MAEL, PADI2, PDK1, PPP1R7, SCN1A, SLAMFI, SSTR2, TNFRSF9, USH2A, VEZF1, and WDR91. Claims 1-6, 9, 12-15, and 20-23 read on the elected species.” This is not found persuasive because Groups I-III fails to disclose a common function. Each method is drawn to specific method for diffuse large B-cell lymphoma prognosis and/or treatment. All of the methods presented do not comprise a significant shared element as each requires a particular set of genes in the gene expression profile, survival outcome assessment, and treatment and/or treatment modification. The mere fact that the methods comprise a similar set of genes in claims 1, 12 and 20 is not sufficient to meet the criteria for unity of invention. The common technical feature has been taught in the prior as documented below in the rejection of claims 1-6 and 9 under 35 U.S.C. 103 as being unpatentable over Staudt et al. (“Staudt”; Patent App. Pub. No. US 20110152115 A1, June 23, 2011).
The requirement is still deemed proper and is therefore made FINAL.
Claims 12-15 and 20-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Groups II and IV, drawn to a method of treating diffuse large B-cell lymphoma in a patient in need thereof; and a method for diffuse large B-cell lymphoma prognosis and treatment in a patient in need thereof, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/08/2025.
Claims 16-19 and 30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group III and V, drawn to a system and a kit, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/08/2025.
Claims Status
Claims 1-6, 9, 12-23 and 30 are pending.
Claims 12-23 and 30 are withdrawn.
Claims 7-8 and 10 are canceled.
Claims 1-6, 9, are currently under examination.
Priority
The present application is the U.S. National Stage of International Patent Application No. PCT/US2021/056774, filed October 27,2021, which claims the priority benefit of U.S. Provisional Patent Application Serial No. 63/105,970, filed October 27, 2020.
Claim Objections
Claim 4 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 1. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim 5 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 2. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 1 and 4 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.
Claims 1 and 4 are indefinite over the limitation “FAM223AIFAM223B”. It is unclear if the gene “FAM223AIFAM223B” is intended to be a single fusion gene or if FAM223A and FAM223B are investigated separately as two different genes.
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 1-6 and 9 are rejected under 35 U.S.C. 101 because the claimed invention is directed towards a natural phenomenon of gene expression in diffuse large B-cell lymphoma and routine and conventional determining a gene expression profile in a biological sample, without significantly more. The claim(s) recite(s) natural phenomena and routine and conventional methods. This judicial exception is not integrated into a practical application because no additional elements integrate the judicial exceptions into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because no additional elements are considered significantly more than the judicial exceptions.
Claim analysis
The instant claim 1 is directed towards: A method for diffuse large B-cell lymphoma prognosis and treatment in a patient in need thereof, said method comprising: determining a first gene expression profile in a biological sample from the patient for at least ALDOC, ASIP, ATP8A1, CD1E, DUSP16, FAF1, FAM223A|FAM223B, GAREM, GNG8, LMO2, LPPR4, LY75, MAEL, PADI2, PDK1, PPP1R7,SCN1A, SLAMF1, SSTR2, TNFRSF9, USH2A, VEZF1, and WDR91; and correlating increased expression levels of said genes with improvement in overall survival outcomes in the patient; and administering a therapeutic treatment to said patient.
The correlation of increased expression levels of gene expression profile to improvement in overall survival outcomes in the patient is a natural phenomenon.
The determining a first gene expression profile in a biological sample from the patient for at least ALDOC, ASIP, ATP8A1, CD1E, DUSP16, FAF1, FAM223A|FAM223B, GAREM, GNG8, LMO2, LPPR4, LY75, MAEL, PADI2, PDK1, PPP1R7,SCN1A, SLAMF1, SSTR2, TNFRSF9, USH2A, VEZF1, and WDR91 is considered to be an active step requiring the analysis of a sample. The active step is routine and conventional as demonstrated by the 35 USC § 103 rejections stated below.
Dependent claims set forth further limitations about the determination of a second gene expression profile, method of detecting gene expression, and determination of first gene expression profile after treatment.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case, the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, natural phenomena.
With regard to claim 1, the claim recites “A method for diffuse large B-cell lymphoma prognosis and treatment in a patient in need thereof, said method comprising: determining a first gene expression profile in a biological sample from the patient for at least ALDOC, ASIP, ATP8A1, CD1E, DUSP16, FAF1, FAM223A|FAM223B, GAREM, GNG8, LMO2, LPPR4, LY75, MAEL, PADI2, PDK1, PPP1R7,SCN1A, SLAMF1, SSTR2, TNFRSF9, USH2A, VEZF1, and WDR91; and correlating increased expression levels of said genes with improvement in overall survival outcomes in the patient; and administering a therapeutic treatment to said patient.” The method of determining the level of expression of a first gene expression profile is routine and conventional. Gene expression naturally changes with improved health in the patient and is thus a natural phenomenon.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? No, there are no additional steps that integrate the claims into a practical application. Although the independent claim 1 recited “administering a therapeutic treatment”, which is of great generality being routine and conventional as demonstrated in the prior art rejections documented below. Furthermore, there is an absence of a verified indication of a particular disease or medical condition, or type of treatment claimed. (See MPEP 2106.04).
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No, there are no additional elements that are significantly more than the judicial exceptions.
Regarding claim 1, the claim requires the routine and conventional active steps of : determining a first gene expression profile in a biological sample from the patient for at least ALDOC, ASIP, ATP8A1, CD1E, DUSP16, FAF1, FAM223A|FAM223B, GAREM, GNG8, LMO2, LPPR4, LY75, MAEL, PADI2, PDK1, PPP1R7,SCN1A, SLAMF1, SSTR2, TNFRSF9, USH2A, VEZF1, and WDR91 to prognose diffuse large B-Cell lymphoma similar to that of Staudt et al. (“Staudt”; Patent App. Pub. No: US 20110152115 A1 June 23, 2011).
Staudt discloses “The present invention discloses methods for identifying, diagnosing, and predicting survival in a lymphoma or lymphoproliferative disorder on the basis of gene expression patterns. The invention discloses a novel microarray, the Lymph Dx microarray, for obtaining gene expression data from a lymphoma sample. The invention also discloses a variety of methods for utilizing lymphoma gene expression data to determine the identity of a particular lymphoma and to predict survival in a subject diagnosed with a particular lymphoma. This information is useful in developing the appropriate therapeutic approach for use with a particular subject.” Thus, the claim does not provide additional steps which are significantly more.
Dependent claims require further limitations about the determination of a second gene expression profile, method of detecting gene expression, and determination of first gene expression profile after treatment which are all routine and conventional based on Staudt et al. (“Staudt”; Patent App. Pub. No: US 20110152115 A1 June 23, 2011).
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.
Claims 1-6 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Staudt et al. (“Staudt”; Patent App. Pub. No. US 20110152115 A1, June 23, 2011).
Staudt discloses “The present invention discloses methods for identifying, diagnosing, and predicting survival in a lymphoma or lymphoproliferative disorder on the basis of gene expression patterns. The invention discloses a novel microarray, the Lymph Dx microarray, for obtaining gene expression data from a lymphoma sample. The invention also discloses a variety of methods for utilizing lymphoma gene expression data to determine the identity of a particular lymphoma and to predict survival in a subject diagnosed with a particular lymphoma. This information is useful in developing the appropriate therapeutic approach for use with a particular subject.”
Claim 2-4, 6 and 9 depend on claim 1. Claim 5 depend on claim 2 which depends on claim 1.
Regarding claims 1-2 and 4-5, Staudt teaches a method comprising “The diagnostic and identification methods of the present invention allow for more precise delineation between these lymphomas, which simplifies the decision of whether to pursue a particular therapeutic option. Likewise, the survival prediction methods disclosed in the present invention also allow for better selection of therapeutic options. A subject with a very low survival predictor score (i.e., very good prognosis) may not receive treatment, but may instead be subjected to periodic check-ups and diligent observation. As survival predictor scores increase (i.e., prognosis gets worse), subjects may receive more intensive treatments. Those subjects with the highest survival predictor scores (i.e., very poor prognosis) may receive experimental treatments or treatments with novel agents.” (Para. 94) and “The samples were …classified into the following lymphoma types based on current diagnostic criteria: … diffuse large B cell lymphomas (DLBCL)” (Para. 103-104) Thus, Staudt teaches a method for diffuse large B-cell lymphoma prognosis and treatment in a patient in need thereof.
Regarding claims 1-2 and 4-5, Staudt teaches a method comprising LMO2, LY75, SLAMF1, TNFRSF9, PDK1, GNG8, ECT2 AND NEK3 (Table 2). Staudt also teaches a method comprising gene expression data obtained using Affymetrix U133A and U133B microarrays” (Para. 77). Staudt teaches a method comprising “A step-up procedure was applied to determine the optimal number of gene signatures to use in the survival predictor model. First, the gene expression signature that was most significantly associated with survival was included in the model. Next, the gene expression signature with the second highest association with survival was added to the model to form a two-component model” (Para. 168). Staudt teaches a method comprising “23 PMBL signature genes” (Para. 40). Furthermore, Staudt teaches a method comprising “Hierarchical clustering is performed to group these genes into gene expression signatures, and the expression of all genes within each signature are averaged to obtain a gene expression signature value for each signature. These gene expression signature values are then used to generate a multivariate survival predictor” (Para. 9; Para. 55). “Affymetrix U133A and U133B” read on a microarray used to determine the expression levels of ALDOC, ASIP, ATP8A1, CD1E, DUSP16, FAF1, FAM223A|FAM223B, GAREM, GNG8, LMO2, LPPR4, LY75, MAEL, PADI2, PDK1, PPP1R7,SCN1A, SLAMF1, SSTR2, TNFRSF9, USH2A, VEZF1, WDR91, ADRA2B, ECT2, ELOVL6, IGSF9, NEK3, PDK4, PES1, PUSL1,TADA2A, and ZMYND19. “23 PMBL signature genes” read on 23 genes to determine first expression profile. Thus, Staudt teaches a method comprising: determining a first gene expression profile in a biological sample from the patient for at least ALDOC, ASIP, ATP8A1, CD1E, DUSP16, FAF1, FAM223A|FAM223B, GAREM, GNG8, LMO2, LPPR4, LY75, MAEL, PADI2, PDK1, PPP1R7,SCN1A, SLAMF1, SSTR2, TNFRSF9, USH2A, VEZF1, and WDR91; and determining a second gene expression profile in said biological sample for at least a second set of genes ADRA2B, ECT2, ELOVL6, IGSF9, NEK3, PDK4, PES1, PUSL1,TADA2A, and ZMYND19.
Regarding claims 1-2 and 4-5, Staudt teaches a method comprising “Gene expression data from Affymetrix U133A and U133B microarrays was obtained for each of the samples. A Cox proportional hazards model was used to identify survival predictor genes whose expression levels were associated with long survival (good prognosis genes) or short survival (poor prognosis genes) in the training set. The correlation between expression and survival for each gene on the microarrays is provided … a Cox coefficient indicating the extent to which a 2-fold increase in expression of a particular gene affects mortality. A positive Cox coefficient indicates increasing mortality with increasing expression of the gene, while a negative Cox coefficient indicates decreasing mortality with increasing expression of the gene” (Para. 161; Para. 167). Thus, Staudt suggests correlating increased expression levels of said genes with improvement in overall survival outcomes in the patient; and correlating low expression levels of said second set of genes with improvement in overall survival outcomes in the patient.
Regarding claims 1-2 and 4-5, Staudt teaches a method comprising “…As survival predictor scores increase (i.e., prognosis gets worse), subjects may receive more intensive treatments. Those subjects with the highest survival predictor scores (i.e., very poor prognosis) may receive experimental treatments or treatments with novel agents. Accurate survival prediction using the methods disclosed herein provides an improved tool for selecting treatment options and for predicting the likely clinical outcome of those options” (Para. 94). Thus, Staudt teaches a method comprising administering a therapeutic treatment to said patient.
Regarding claim 3, Staudt teaches a method wherein “a biopsy sample is obtained from the subject… belonging to a lymph node” (Para. 15). Thus, Staudt teaches a method wherein said sample is lymph node tissue.
Regarding claim 6, Staudt teaches a method wherein “the gene expression data used in this method is obtained using a microarray.” (Para. 13). Thus, Staudt teaches a method wherein said first gene expression profile is determined by a system configured to assay a plurality of molecular targets in the biological sample to detect gene expression levels for said first set of genes, wherein said system is selected from the group consisting of microarray, PCR, immunoassay, quantitative PCR, and next- generation sequencing.
Regarding claim 9, Staudt teaches a method wherein “All patients from whom the samples were derived had been treated with anthracycline-containing multiagent chemotherapy protocols, with some patients additionally receiving radiation therapy. The training set was profiled for gene expression” (Para. 206). Thus, Staudt teaches a method further comprising repeating the determination of the first gene expression profile after administering said treatment to yield an updated first gene expression profile, and comparing the first gene expression profile to the updated first gene expression profile to determine efficacy of said treatment.
Therefore, the invention as recited in claims 1-6 and 9 is prima facie obvious over the prior art Staudt et al. One of ordinary skill in the art would have had a reasonable expectation of success given the lack of novelty. It would have been obvious to provide a method for diffuse large B-cell lymphoma prognosis and treatment in a patient in need thereof according to the limitations of the instant application claims 1-6 and 9 based on Staudt et al. (Patent App. Pub. No. US 20110152115 A1).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's
disclosure: Skog et al. (“Skog”; Patent App. Pub. US 20140045915 A1, Feb. 13, 2014) -Table 3; Para. 104; Para. 119; Para. 126; Para 69. (Claims 1-6 and 9)
No claims are in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KENDRA R VANN-OJUEKAIYE whose telephone number is (571)270-7529. The examiner can normally be reached M-F 9:00 AM- 5:00 PM.
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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682