DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. This action is in response to the papers filed February 5, 2026. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicant's amendments. Any rejections or objections not reiterated herein have been withdrawn. This action is made FINAL.
Applicant’s election without traverse of Group I in the reply filed on October 9, 2025 is reiterated for the record.
Claims 1, 8-16, and 20 are currently pending.
Claims 14-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on October 9, 2025.
Duplicate Claims, Warning
3. Applicant is advised that should claim 1 be found allowable, claim 16 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. 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 § 101
4. 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, 8-13, 16, and 20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims recite a judicial exception that is not integrated into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The claim analysis is set forth below.
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite abstract ideas.
The claims recite a step of “identifying” the subject as being likely to benefit from anti-tumor necrosis factor when the presence of the HLA-DR*0404 variant and the two T alleles of SNP 763361 are detected in the biological sample (clm 1). The “identifying” step broadly encompasses a mental processes. For example, one may “identify” the subject as being likely to respond to the anti-TNF therapy by thinking about the presence of the HLA-DR*0404 variant and the two T alleles of SNP 763361. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgment, opinions) are considered to be abstract ideas.
The claims recite a step of “evaluating” the DAS28 score of the subject (clm 8). The “evaluating” step broadly encompasses a mental processes. For example, one may “evaluate” the DAS28 score by reading the subjects score on a medical record and then thinking about it. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgment, opinions) are considered to be abstract ideas.
The instant claims recite a law of nature.
The claims recite a step of “identifying” the subject as being likely to benefit from anti-tumor necrosis factor when the presence of the HLA-DR*0404 variant and the two T alleles of SNP 763361 are detected in the biological sample (clm 1). The claims recite a correlation between the markers and response to anti-TNF therapy. This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological
environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
In addition to the judicial exceptions, claim 1 requires steps of: obtaining a biological sample from a subject having rheumatoid arthritis, detecting the presence of the HLA-CRB*0404 variant, and detecting the presence of two thymine alleles at SNP rs763361. These steps are NOT considered to integrate the judicial exceptions into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exceptions.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition to the judicial exceptions, claim 1 requires steps of: obtaining a biological sample from a subject having rheumatoid arthritis, detecting the presence of the HLA-CRB*0404 variant, and detecting the presence of two thymine alleles at SNP rs763361. These steps do NOT amount to significantly more because they simply append well understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions.
The steps are recited at a high level of generality. Obtaining a biological sample in order to perform tests is well understood, routine, and conventional activity for those in the field of biology. Detecting the presence of variants and of a SNP in a biological sample merely instructs a scientist to use any technique known in the art for detecting nucleic acids or proteins. The claims do not require the use of any particular non-conventional reagents. When recited at this high level of generality, there is no meaningful limitation that distinguishes this step from well understood, routine, and conventional activities engaged in by scientists prior to applicants invention and at the time the application was filed.
Additionally the teachings in the specification demonstrate the well understood, routine, conventional nature of additional elements because it teaches that the additional elements are well known or commercially available. For example the specification teaches the following:
[0124] All genotyping was performed by biochip array technology (such as custom Rheumastrat™ biochip array technology (Evidence Analyser™, Randox Laboratories Ltd.). Genotyping was confirmed by the polymerase chain reaction-sequence-specific oligonucleotide probe (PCR-SSOP) method described by McGeough C M et al. (2012), and Middleton D et al. (2005).
Further it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For the reasons set forth above the claims are not directed to patent eligible subject matter.
Response To Arguments
5. In the response the Applicants traversed the rejection under 35 USC 101. The response states that claims 1 and 16 have been amended to recite methods for identifying a subject having rheumatoid arthritis that is likely to benefit from anti-tumor necrosis factor therapy by detecting HLA-DRB*0404 and detecting the presence of two thymine alleles at single nucleotide polymorphism rs763361. The claims, although being directed to processes, do not claim a judicial exception as they are not directed to a law of nature, an abstract idea, or a natural phenomenon. Should the Office consider the identification of certain biological characteristics related to the likelihood that a subject with rheumatoid arthritis would respond to anti-tumor necrosis factor therapy, the biological characteristics themselves are not being claimed, only their identification. In addition, steps a, b, and c when considered together provide additional elements beyond any judicial exception. Applicant would also note the claimed methods are an improvement in the clinical arts because prior to the methods as claimed the only way to determine whether a subject with rheumatoid arthritis would benefit from anti-tumor necrosis factor therapy was to treat the patient and see if they responded.
These arguments have been fully considered but are not persuasive. Claims 1 and 16 as amended still recite at least two judicial exceptions identified in the Guidance. First the claims recite a natural correlation of the HLA-DRB*0404 and rs763361 and the likely benefit from anti-TNF therapy. Secondly Claims 1 and 16 recite abstract ideas. The step of “identifying” broadly encompasses a mental processes because one may “identify” the subject as being likely to respond to the anti-TNF therapy by thinking about the presence of the HLA-DR*0404 variant and the two T alleles of SNP 763361. Having determined that the claims recite a natural law, we next examine whether there are additional elements beyond the natural law that integrate the judicial exceptions into a practical application. In addition to the judicial exceptions we only have steps a-c to consider since step d is the judicial exception. Steps a-c merely add insignificant extra-solution activity (data gathering) to the judicial exceptions. Regarding the improvement argument, it is noted that if the judicial exception itself is the purported improvement, such as the recognition of the correlation between a set of markers and response to anti-TNF therapy, then the claim is directed to the judicial exception, not an eligible improvement to a technology or technical field through integration of the judicial exception into a system or process. Steps a-c are NOT considered to integrate the judicial exceptions into a practical application. Additionally steps a-c do NOT amount to significantly more because they simply append well understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions. The rejection is maintained.
Claim Rejections - 35 USC § 103
6. 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.
7. Claims 1, 8, 10, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Tan (Ann Rheum Dis 2010; 69 1029-1035) in view of Criswell (Arthritis and Rheumatism Vol 50 No 9 September 2004 pages 2750-2756).
Regarding Claim 1 Tan teaches that they investigated the association of markers within confirmed RA susceptibility loci with the response to anti-TNF treatment. Tan teaches that biological sample were obtained from RA patients treated with anti-TNF drugs. Tan teaches that the samples were genotyped using the Sequenom MassArray iPLEX system. Tan teaches that SNP rs763361 had a statistically significant association with the response to anti-TNF treatment. Tan teaches that for SNP rs763361, the TT genotype was associated with a higher response to treatment as compared to the TC or CC genotypes (abstract, page 1030, Table 3). Thus Tan teaches a method for identifying a subject having RA that is likely to benefit from anti-TNF therapy comprising the steps of: obtaining a biological sample from the subject having RA; detecting the presence of two thymine alleles at rs763361; and identifying the subject as being likely to benefit from anti-TNF therapy when two T alleles of rs763361 are detected in the sample.
Regarding Claim 8 Tan teaches a method that further comprises evaluating the DAS28 score of the subject (abstract).
Regarding Claim 10 Tan teaches that genotyping was performed using the Sequenom MassArray iPLEX system (page 1030, col 1).
Tan does not teach a method further comprising detecting the presence of the HLA-DRB1 *0404 variant in a biological sample from a subject with RA (clm 1). Tan does not teach identifying the subject as being likely to benefit from anti-TNF therapy when the HLA-DRB1 *0404 variant is detected (clm 1).
However Criswell teaches that they conducted a study to examine the roles of specific genetic polymorphisms as predictors of response to treatment of early rheumatoid arthritis (RA). Methods. The enrolled subjects were given methotrexate, etanercept (10mg biweekly) or etanercept (25mg biweekly). The primary outcome was achievement of 50% improvement in disease activity according to the criteria of the American College of Rheumatology (ACR50 response) after 12 months of treatment. Subjects were genotyped for HLA–DRB1 alleles and polymorphisms in the following genes: TNF,LTA, TNFRSF1A, TNFRSF1B, FCGR2A, FCGR3A, and FCGR3B. Criswell teaches that the presence of 2 HLA–DRB1 alleles encoding the shared epitope (SE) (compared with 1 or 0 copies) was associated with response to treatment with standard-dose etanercept. Among Caucasian patients, 2 extended haplotypes that included the HLA–DRB1 alleles *0404 and *0101 and 6 single-nucleotide polymorphisms in the LTA–TNF region were associated with response to treatment. Criswell teaches that genetic variation in the HLA–DRB1 and the LTA–TNF regions is significantly associated with response to treatment of early RA (abstract).
Accordingly, 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 Tan by further detecting the presence of HLA-DRB1 *0404 as suggested by Criswell. In the instant case, Tan and Criswell were both interested in finding markers that predict the response to anti-TNF treatment of rheumatoid arthritis. Tan teaches that the TT genotype (wildtype) of SNP rs763361 was associated with a higher response to treatment with anti-TNF therapy. Criswell teaches that the presence of the HLA–DRB1 allele *0404 was associated with a higher response to treatment with entancerpt (which is a type of anti-TNF therapy). The skilled artisan would have been motivated to combine the teachings of the prior arts to achieve the claimed invention which requires detection of both of these markers and there would have been a reasonable expectation of success that the combination of these two markers would aid in being able to identify additional patients that are likely to respond to anti-TNF therapy for rheumatoid arthritis.
8. Claims 9, 11, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Tan (Ann Rheum Dis 2010; 69 1029-1035) in view of Criswell (Arthritis and Rheumatism Vol 50 No 9 September 2004 pages 2750-2756) as applied to claim 1 above and in further view of Nelson (US 2015/0024391 January 22, 2015).
The teachings of Tan and Criswell are presented above.
The combined references do not teach a method that comprises a polymerase chain reaction method (clm 9). The combined references do not teach a method wherein the detecting step comprises contacting the sample with a primer consisting of a nucleic acid sequence defined in SEQ ID NO: 3 (clm 11). The combined references do not teach a method wherein the sample is blood (clm 13).
However Nelson teaches primers specific for HLA alleles that are used to amplify these markers (abstract). Nelson teaches the sample can be blood (para 0026). Nelson teaches quantitative PCR (para 0028). Nelson discloses SEQ ID NO: 13 which is 100% identical to SEQ ID NO: 3 (See Table 1).
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Accordingly, 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 Tan and Criswell by obtaining DNA from a blood sample and performing PCR amplification using SEQ ID NO: 3 to detect HLA alleles as suggested by Nelson. One of skill in the art would have been motivated to use the primer of Nelson since it was already designed and validated in methods for amplifying and detecting HLA alleles. Further methods of obtaining DNA from blood samples and performing PCR to genotype HLA alleles was conventional in the art at the time of the invention as demonstrated by Nelson.
9. Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Tan (Ann Rheum Dis 2010; 69 1029-1035) in view of Criswell (Arthritis and Rheumatism Vol 50 No 9 September 2004 pages 2750-2756) in view of Meissner (US 2019/0309259 Pub Oct 10, 2019).
The teachings of Tan and Criswell are presented above.
The combined references do not teach a method wherein the detecting comprises contacting the sample with at least one primer consisting of a nucleic acid sequence defined by SEQ ID NO: 5.
However Meissner discloses a nucleic acid sequence (SEQ ID NO: 354067) that is 100% identical to SEQ ID NO: 5.
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Accordingly, 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 Tan and Criswell by detecting rs763361 using a primer comprising SEQ ID NO: 5 as suggested by Meissner. One of skill in the art would have been motivated to use the primer of Nelson since it was already designed and validated in methods for amplifying and detecting CD266 alleles.
10. Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Tan (Ann Rheum Dis 2010; 69 1029-1035) in view of Criswell (Arthritis and Rheumatism Vol 50 No 9 September 2004 pages 2750-2756) and Nelson (US 2015/0024391 January 22, 2015) as applied to claims 1 and 11 above and in further view of Meissner (US 2019/0309259 Pub Oct 10, 2019).
The teachings of Tan, Criswell, and Nelson are presented above.
The combined references do not teach a method wherein the detecting comprises contacting the sample with at least one primer having a nucleic acid sequence defined by SEQ ID NO: 5.
However Meissner discloses a nucleic acid sequence (SEQ ID NO: 354067) that is 100% identical to SEQ ID NO: 5.
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Accordingly, 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 Tan, Criswell, and Nelson by detecting rs763361 using a primer comprising SEQ ID NO: 5 as suggested by Meissner. One of skill in the art would have been motivated to use the primer of Nelson since it was already designed and validated in methods for amplifying and detecting CD266 alleles.
Response To Arguments
11. In the response the Applicants traversed the rejection under 35 USC 103. Regarding Claims 1, 8, 10, and 16 the Applicants argue that the method of claim 1 provides an unexpected, synergistic improvement in identifying rheumatoid arthritis subjects likely to benefit from anti-tumor necrosis factor therapy. In particular, it is disclosed in the present application that the presence of both the HLA-DRB*0404 variant and two T alleles of SNP rs763361 in the biological sample from the RA subject is a valuable indicator that the subject is likely to benefit from anti-TNF therapy. The Applicants argue that the cited documents do not disclose or teach the benefits of testing for the presence of both the HLA-DRB*0404 variant and two T alleles of SNP rs763361 from the RA subject. The Applicants argue that Tan teaches a different way (by combining AFF3 and CD226) to improve the test for likely response to anti-TNF treatment in RA patients. The skilled person reading Tan would not be motivated to look further for a different way to improve the test. The Applicants argue that Criswell does not teach a method comprising testing for two different markers, or wherein a marker is two T alleles at SNP rs763361. They argue that the skilled person considering both Tan and Criswell would not be motivated to test for the specific combination of the presence of both the HLA-DRB*0404 variant and two T alleles of SNP rs763361. Tan teaches a different combination test that has already been verified. Whether or not a new test comprising a new combination of markers would be a more useful test is highly unpredictable, and so the skilled person would not have a reasonable expectation of success in improving the test of either Tan or Criswell by devising a new combination test. Furthermore, the skilled person would have no reason to select the specific combination of markers of the present invention from the disclosures of Tan and Criswell.
These arguments have been fully considered but are not found persuasive. The Applicants argue that the combination of the two markers provides an unexpected, synergistic improvement in identifying rheumatoid arthritis subjects likely to benefit from anti-tumor necrosis factor therapy, however they have not submitted any evidence demonstrating this. MPEP 716.01(c)(II) recites the following:
Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
The Applicants have not met the burden of establishing that the combination of the two markers results in a unexpected, synergistic improvement. Regarding synergism MPEP 716.02(a) recites the following:
Evidence of a greater than expected result may also be shown by demonstrating an effect which is greater than the sum of each of the effects taken separately (i.e., demonstrating “synergism”). Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). However, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (Evidence showing greater than additive sweetness resulting from the claimed mixture of saccharin and L-aspartyl-L-phenylalanine was not sufficient to outweigh the evidence of obviousness because the teachings of the prior art lead to a general expectation of greater than additive sweetening effects when using mixtures of synthetic sweeteners.).
The Examiner maintains that the skilled artisan would have been motivated to combine the teachings of Tan and Criswell which would result in a method which detects both of SNP rs763361 and HLA-DRB*0404 in a sample from a subject with rheumatoid arthritis since both of these markers known to be correlated with the response to anti-TNF therapy for the treatment of rheumatoid arthritis. There would have been a reasonable expectation of success that the combination of these two markers would aid in being able to identify additional patients that are likely to respond to anti-TNF therapy for rheumatoid arthritis.
Regarding Claims 9, 11, and 12 the Applicants argue that the prior art of Nelson does not
fill the deficiencies of Tan and Criswell noted above with respect to claim 1. Regarding Claim 12, the Applicants argue that the prior art of Meissner does not fill the deficiencies of Tan and Criswell noted above with respect to claim 1. Regarding Claim 20 the Applicants argue that the prior arts of Nelson and Meissner do not fill the deficiencies of Tan and Criswell noted above with respect to claim 1.
This argument has been fully considered but is not persuasive. The Applicants arguments regarding what is missing in the combination of Tan and Criswell have been fully addressed above. The response to Applicants arguments, as set forth above, applies equally to these additional grounds of rejection.
12. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682