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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/30/2025 has been entered.
Claims Status
Claims 19, 21, 22, 24-26, 28, 30, & 32 filed on 12/30/2025 are pending. Claims 30-34 are currently under examination directed to the elected species of HLA-A and HLA-G (see response dated 12/23/2024). Claims 31, 33, & 34 are withdrawn from consideration as being drawn to a non-elected invention. All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections are either newly applied, as necessitated by amendment, or are reiterated. They constitute the complete set being presently applied to the instant application. Response to Applicant’s argument follow. This action is Non-FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 101
Claims 19, 21, 22, 24, 25, 30, & 32 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature and an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
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. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014). See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to methods and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claimed invention recites a method of determining individual HLA patterns of a tumor in a subject by determining and comparing the expression levels of a classical HLA gene and a non-classical HLA gene. This recitation is a natural correlation between the expression levels of a classical and non-classical HLA gene and the HLA pattern of a tumor. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action. The claimed invention also recites “reporting the determining HLA isoforms to a clinician or patient” which broadly encompasses reading a report and recites “determining a first expression level … determining at least a second expression level” and “comparing the determined first and second expression levels” which is a recitation of an abstract idea because it encompasses conclusions and determinations which can occur entirely within the mind. It is therefore determined that the claims are directed to judicial exceptions.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
The claims recite steps of comparing determined first and second expression levels to obtain an individual HLA pattern, comparison of the expression levels through an expression level ratio, and use of nucleic acid molecule(s) as primers or probes, however this does not integrate the JE into a practical application because it is a mere data gathering step to use the correlation and does not add a meaningful limitation to the method.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
In the instant situation, the steps of determining a first and at least a second expression level are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. This step is not only a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Applicant is reminded that in Mayo, the Court found that “[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Further "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law”. Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at ___ (slip op., at 14) (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ . . . adding ‘insignificant post-solution activity’” (quoting Diehr, supra, at 191–192)). The Court also summarized their holding by stating “[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.” Therefore these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than the determination that a natural correlation/phenomena exists. Any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 102
Claim(s) 19, 21, 22, 24, 25, 30, & 32 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Willers (Willers et al.; The Journal of Investigative Dermatology, Vol. 117, pages 1498-1504, August 2001), as evidenced by Carosella (Carosella, Dausset, & Kirszenbaum; Trends Immunology Today, Vol. 9, pages 407-409, September 1996) and as evidenced by Cereb (Cereb et al., Tissue Antigens, Vol. 45, pages 1-11, November 1994).
Regarding newly amended claim 19, it is noted, the instant specification, pg. 13, broadly teaches that determining HLA isoforms based on the comparison of the first and second expression levels encompasses if the expression level of a region encoding a portion of a first exon exceeds the expression level of a region encoding a portion of a second exon. Due to this, for the purposes of this rejection, the examiner is interpreting determining HLA isoforms based on the comparison of the first and second expression levels to encompass the comparison of an expression levels of a region encoding a portion of a first exon and a portion of a second exon.
Willers teaches the detection of mRNA expression of classical HLA genes (HLA-A and HLA-B) (determining a first expression level of RNA transcript encoding a first region of a first HLA gene) and of a non-classical HLA gene (HLA-G) (determining at least a second expression level of RNA transcript of at least one second HLA gene) and comparison of the expression levels between the classical HLA genes (first HLA gene) and non-classical HLA gene (second HLA gene) (pg. 1498 abstract lines 14-25; pg. 1499-1500 paragraph bridging pg. 1499 & 1500 lines 11-12 & 36-39; pg. 1501 paragraph bridging column 1 & 2 lines 30-33; Table I). In addition, Willers teaches the expression levels of the classical HLA-A and HLA-B genes are measured from the 3’ and 5’ untranslational (UT) region of the HLA-A and HLA-B gene segments which indicates no presence of an exon-exon boundary (first region comprises no exon-exon boundary) (pg. 1499-1500 paragraph bridging pg. 1499 & pg. 1500 lines 4-12; Table I). Willers also teaches the expression level of the non-classical HLA-G gene is measured from exon 3 to exon 5 which indicates the presence of an exon-exon boundary (the second region comprises an exon-exon boundary and primers span exon-exon with forward primer in one exon and reverse primer in another exon) (determining HLA isoforms based on the comparison of expression levels of a first region (expression of a first expression level encoding a region of a first classical HLA gene) and a second region (expression of a second expression level encoding a second non-classical HLA gene)) (Table I) and further teaches that these expression levels represent important criteria in selecting patients for specific therapies (reporting the determined HLA isoforms based on the comparison of expression levels in first and second region to clinician or patient to determine method of treatment) (pg. 1502-1503 paragraph bridging pg. 1502 & 1503 9-13).
Regarding claim 21, Willers teaches measuring the expression of the 3’ and 5’ UT region of the classical HLA-A gene (pg. 1499-1500 paragraph bridging pg. 1499 & pg. 1500 lines 4-12; Table I) which inherently encompasses a signal peptide region of a HLA group, as evidenced by Cereb (pg. 2 of Cereb paragraph bridging column 1 & 2 lines 23-27). Willers also teaches the expression level of the non-classical HLA-G gene is measured from exon 3 to exon 5 (Table I) in which exon 5 of HLA-G inherently encompasses a transmembrane region, as evidenced by Carosella (pg. 407 of Carosella paragraph bridging column 2 and 3 lines 8-14).
Regarding claim 22, the specification of the instant application broadly defines what is considered to be predominately soluble or membrane-bound. For example, the paragraph bridging pg. 12 & 13 in the specification of the instant application states that “if the expression level of a region encoding a signal peptide region of a HLA group exceeds the expression level of a region encoding a transmembrane region of the HLA group, it may be determined that the individual HLA pattern is predominantly soluble. If the expression level of a region encoding a transmembrane region of a HLA group is essentially equal to or exceeds the expression level of a region encoding a signal peptide of the HLA group, it may be determined that the individual HLA pattern is predominantly membrane-bound”. Due to this, for the purposes of this rejection, the examiner is interpreting determining whether the individual HLA pattern is predominantly soluble or membrane-bound to encompass the comparison of an expression level of a region encoding a signal peptide region of a HLA group and an expression level of a region encoding a transmembrane region of a HLA group.
Willers teaches the comparison of the expression level of classical HLA-A gene, which inherently encompasses a signal peptide region, as evidenced by Cereb (pg. 2 of Cereb paragraph bridging column 1 & 2 lines 23-27), to the expression level of non-classical HLA-G from exon 3 to exon 5 (pg. 1498 abstract lines 14-25; pg. 1499-1500 paragraph bridging pg. 1499 & 1500 lines 11-12 & 36-39; pg. 1501 paragraph bridging column 1 & 2 lines 30-33; Table I) in which exon 5 of HLA-G inherently encompasses a transmembrane region as evidenced by Carosella (pg. 407 of Carosella paragraph bridging column 2 and 3 lines 8-14).
Regarding claim 24, Willers teaches measuring the expression level of two classical HLA genes, HLA-A and HLA-B, (determining one or more further expression levels) and the expressional level of a non-classical HLA gene, HLA-G (pg. 1498 abstract lines 14-25; pg. 1499-1500 paragraph bridging pg. 1499 & 1500 lines 11-12 & 36-39; pg. 1501 paragraph bridging column 1 & 2 lines 30-33; Table 1).
Regarding claim 25, Willers teaches the comparison of expression levels in the form of a ratio between classical and non-classical HLA genes (pg. 1501 paragraph bridging column 1 & 2 lines 23-33).
Regarding claim 30, Willers teaches the classical HLA genes are HLA-A and HLA-B (pg. 1498 abstract lines 14-25; pg. 1499-1500 paragraph bridging pg. 1499 & 1500 lines 11-12 & 36-39; pg. 1501 paragraph bridging column 1 & 2 lines 30-33; Table 1).
Regarding claim 32, Willers teaches the non-classical HLA gene is HLA-G (pg. 1498 abstract lines 14-25; pg. 1499-1500 paragraph bridging pg. 1499 & 1500 lines 11-12 & 36-39; pg. 1501 paragraph bridging column 1 & 2 lines 30-33; Table 1).
Response to Arguments
It is noted that the arguments, at page 7 of the response, traverses the reference Willers originally applied in 35 USC 103. Further, these arguments will be addressed in so far as they apply to the rejections applied under 35 USC 102(a)(1), as discussed above, as necessitated by amendment.
The response traverses the rejection. The response asserts that independent claim 19 is amended to recite a method of determining individual HLA patterns of a tumor in a subject omitting reference to the production of a therapeutic and amended to specify that the second region (or both the first and second region) comprises use of exon-exon-boundary-spanning primers and that the cited references, alone or in combination, fail to teach or suggest a method having these features. Further, the response asserts while Willers may describe differential transcription of classical and nonclassical HLA genes in cancer cells, the reference lacks any teaching related to the use of exon-exon-boundary-spanning primers or comparing the results from boundary vs. non-boundary assays to infer HLA isoforms and instead, the assays disclosed in Willers employ intron-spanning primers. This argument has been thoroughly reviewed but was not found persuasive. First, the newly added limitation of “exon-exon-boundary-spanning primers” in amended claim 19 is not defined in the instant specification and broadly reads on a forward primer in one exon (e.g. exon 3 of HLA-G as taught in Willers at Table I) and a reverse primer in another exon (e.g. exon 5 of HLA-G as taught in Willers at Table I) (primers that span across exons, e.g. span across exon 3 to exon 5 of HLA-G as taught in Willers). Further, the response does not provide any indication as to how the primers in the response are distinguished from the primers taught in Willers.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Claim Rejections - 35 USC § 103
Claim(s) 26 & 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Willers (Willers et al.; The Journal of Investigative Dermatology, Vol. 117, pages 1498-1504, August 2001), as evidenced by Carosella (Carosella, Dausset, & Kirszenbaum; Trends Immunology Today, Vol. 9, pages 407-409, September 1996) and as evidenced by Cereb (Cereb et al., Tissue Antigens, Vol. 45, pages 1-11, November 1994), as applied to claims 19, 21, 22, 24, 25, 30, & 32 above, and further in view of GenBank Accession Number AF117228 (May 1999).
The teachings of Willers with respect claim 19 is discussed above and incorporated herein.
Regarding amended claim 26, Willers fails to teach determining the first or second expression level comprises using nucleic acid molecule(s) consisting of one of SEQ ID Nos 1-3, 8-17, or 19-27 as primers or probes.
The GenBank Accession Number AF117228 teaches the nucleic acid sequence of SEQ ID no. 1 in the instant application (position 3768 to position 3797 from AF117228), the nucleic acid sequence of SEQ ID no. 2 in the instant application (position 3811 to position 3846 from AF117228), and the nucleic acid sequence of SEQ ID no. 3 in the instant application (position 3921 to position 3900 from AF117228).
Willers and GenBank Accession Number AF117228 are considered to be analogous to the claimed invention because they are all in the same field of classification of HLA. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of determining an individual HLA expression pattern with primers or probes as taught in Willers to incorporate the development and use of primer or probes according to GenBank Accession Number AF117228 because it is obvious to develop any primer or probe from a known gene sequence.
Regarding claim 28, Willers teaches the detection of mRNA expression of classical HLA genes (HLA-A and HLA-B) and of a non-classical HLA gene (HLA-G) (and comparison of the expression levels between the classical HLA genes (first HLA gene) and non-classical HLA gene (second HLA gene) (identifying a molecular subtype of the tumor) (pg. 1498 abstract lines 14-25; pg. 1499 column 1 1st full paragraph lines 1-5; pg. 1499-1500 paragraph bridging pg. 1499 & 1500 lines 11-12 & 36-39; pg. 1501 paragraph bridging column 1 & 2 lines 30-33; Table I).
Claim(s) 19, 21, 22, 24, 25, 30, & 32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Willers (Willers et al.; The Journal of Investigative Dermatology, Vol. 117, pages 1498-1504, August 2001), in view of Wang (Wang et al.; PNAS, Vol. 109, pages 8676-8681, May 2012), as evidenced by Carosella (Carosella, Dausset, & Kirszenbaum; Trends Immunology Today, Vol. 9, pages 407-409, September 1996) and as evidenced by Cereb (Cereb et al., Tissue Antigens, Vol. 45, pages 1-11, November 1994).
Regarding newly amended claim 19, it is noted, the instant specification, pg. 13, broadly teaches that determining HLA isoforms based on the comparison of the first and second expression levels encompasses if the expression level of a region encoding a portion of a first exon exceeds the expression level of a region encoding a portion of a second exon. Due to this, for the purposes of this rejection, the examiner is interpreting determining HLA isoforms based on the comparison of the first and second expression levels to encompass the comparison of an expression levels of a region encoding a portion of a first exon and a portion of a second exon.
Willers teaches the detection of mRNA expression of classical HLA genes (HLA-A and HLA-B) (determining a first expression level of RNA transcript encoding a first region of a first HLA gene) and of a non-classical HLA gene (HLA-G) (determining at least a second expression level of RNA transcript of at least one second HLA gene) and comparison of the expression levels between the classical HLA genes (first HLA gene) and non-classical HLA gene (second HLA gene) obtained from melanoma cells from a patient (obtaining a biological sample from a subject) (pg. 1498 abstract lines 14-25; pg. 1499 column 1 1st full paragraph lines 1-5; pg. 1499-1500 paragraph bridging pg. 1499 & 1500 lines 11-12 & 36-39; pg. 1501 paragraph bridging column 1 & 2 lines 30-33; Table I). In addition, Willers teaches the expression levels of the classical HLA-A and HLA-B genes are measured from the 3’ and 5’ untranslational (UT) region of the HLA-A and HLA-B gene segments which indicates no presence of an exon-exon boundary (first region comprises no exon-exon boundary) (pg. 1499-1500 paragraph bridging pg. 1499 & pg. 1500 lines 4-12; Table I). Willers also teaches the expression level of the non-classical HLA-G gene is measured from exon 3 to exon 5 which indicates the presence of an exon-exon boundary (the second region comprises an exon-exon boundary and primers span exon-exon with forward primer in one exon and reverse primer in another exon) (determining HLA isoforms based on the comparison of expression levels of a first region (expression of a first expression level encoding a region of a first classical HLA gene) and a second region (expression of a second expression level encoding a second non-classical HLA gene)) (Table I) and further teaches that these expression levels represent important criteria in selecting patients for specific therapies (reporting the determined HLA isoforms based on the comparison of expression levels in first and second region to clinician or patient to determine method of treatment) (pg. 1502-1503 paragraph bridging pg. 1502 & 1503 9-13).
Wang teaches a method of HLA typing a variety of HLA genes and their alleles through amplification and sequencing through PCR primers designed to capture multiple exons of different HLA genes (use of exon-exon-boundary-spanning primers), for example a primer for HLA-A and HLA-B designed to amplify from exon 1 to exon 7 (abstract lines 1-12; pg. 8677 column 1 1st full paragraph lines 1-7; Fig. 1). In addition, Wang teaches that this method is high-resolution and cost-effective method to amplify and sequence HLA genes and their many alleles (abstract lines 1-12).
Willers and Wang are considered to be analogous to the claimed invention because they are all in the same field of amplification of HLA genes. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of determining expression levels between a classical and non-classical HLA gene to determine an individual HLA expression pattern in Willers to incorporate the use of exon-exon-boundary-spanning primers for HLA genes as taught in Wang because Wang teaches that doing so would provide a high-resolution and cost-effective method for amplifying HLA genes and their many alleles.
Regarding claim 21, Willers teaches measuring the expression of the 3’ and 5’ UT region of the classical HLA-A gene (pg. 1499-1500 paragraph bridging pg. 1499 & pg. 1500 lines 4-12; Table I) which inherently encompasses a signal peptide region of a HLA group, as evidenced by Cereb (pg. 2 of Cereb paragraph bridging column 1 & 2 lines 23-27). Willers also teaches the expression level of the non-classical HLA-G gene is measured from exon 3 to exon 5 (Table I) in which exon 5 of HLA-G inherently encompasses a transmembrane region, as evidenced by Carosella (pg. 407 of Carosella paragraph bridging column 2 and 3 lines 8-14).
Regarding claim 22, the specification of the instant application broadly defines what is considered to be predominately soluble or membrane-bound. For example, the paragraph bridging pg. 12 & 13 in the specification of the instant application states that “if the expression level of a region encoding a signal peptide region of a HLA group exceeds the expression level of a region encoding a transmembrane region of the HLA group, it may be determined that the individual HLA pattern is predominantly soluble. If the expression level of a region encoding a transmembrane region of a HLA group is essentially equal to or exceeds the expression level of a region encoding a signal peptide of the HLA group, it may be determined that the individual HLA pattern is predominantly membrane-bound”. Due to this, for the purposes of this rejection, the examiner is interpreting determining whether the individual HLA pattern is predominantly soluble or membrane-bound to encompass the comparison of an expression level of a region encoding a signal peptide region of a HLA group and an expression level of a region encoding a transmembrane region of a HLA group.
Willers teaches the comparison of the expression level of classical HLA-A gene, which inherently encompasses a signal peptide region, as evidenced by Cereb (pg. 2 of Cereb paragraph bridging column 1 & 2 lines 23-27), to the expression level of non-classical HLA-G from exon 3 to exon 5 (pg. 1498 abstract lines 14-25; pg. 1499-1500 paragraph bridging pg. 1499 & 1500 lines 11-12 & 36-39; pg. 1501 paragraph bridging column 1 & 2 lines 30-33; Table I) in which exon 5 of HLA-G inherently encompasses a transmembrane region as evidenced by Carosella (pg. 407 of Carosella paragraph bridging column 2 and 3 lines 8-14).
Regarding claim 24, Willers teaches measuring the expression level of two classical HLA genes, HLA-A and HLA-B, (determining one or more further expression levels) and the expressional level of a non-classical HLA gene, HLA-G (pg. 1498 abstract lines 14-25; pg. 1499-1500 paragraph bridging pg. 1499 & 1500 lines 11-12 & 36-39; pg. 1501 paragraph bridging column 1 & 2 lines 30-33; Table 1).
Regarding claim 25, Willers teaches the comparison of expression levels in the form of a ratio between classical and non-classical HLA genes (pg. 1501 paragraph bridging column 1 & 2 lines 23-33).
Regarding claim 30, Willers teaches the classical HLA genes are HLA-A and HLA-B (pg. 1498 abstract lines 14-25; pg. 1499-1500 paragraph bridging pg. 1499 & 1500 lines 11-12 & 36-39; pg. 1501 paragraph bridging column 1 & 2 lines 30-33; Table 1).
Regarding claim 32, Willers teaches the non-classical HLA gene is HLA-G (pg. 1498 abstract lines 14-25; pg. 1499-1500 paragraph bridging pg. 1499 & 1500 lines 11-12 & 36-39; pg. 1501 paragraph bridging column 1 & 2 lines 30-33; Table 1).
Claim(s) 26 & 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Willers (Willers et al.; The Journal of Investigative Dermatology, Vol. 117, pages 1498-1504, August 2001) and Wang (Wang et al.; PNAS, Vol. 109, pages 8676-8681, May 2012), as evidenced by Carosella (Carosella, Dausset, & Kirszenbaum; Trends Immunology Today, Vol. 9, pages 407-409, September 1996) and as evidenced by Cereb (Cereb et al., Tissue Antigens, Vol. 45, pages 1-11, November 1994), as applied to claims 19, 21, 22, 24, 25, 30, & 32 above, and further in view of GenBank Accession Number AF117228 (May 1999).
The teachings of Willers and Wang with respect claim 19 is discussed above and incorporated herein.
Regarding amended claim 26, Willers and Wang fails to teach determining the first or second expression level comprises using nucleic acid molecule(s) consisting of one of SEQ ID Nos 1-3, 8-17, or 19-27 as primers or probes.
The GenBank Accession Number AF117228 teaches the nucleic acid sequence of SEQ ID no. 1 in the instant application (position 3768 to position 3797 from AF117228), the nucleic acid sequence of SEQ ID no. 2 in the instant application (position 3811 to position 3846 from AF117228), and the nucleic acid sequence of SEQ ID no. 3 in the instant application (position 3921 to position 3900 from AF117228).
Willers, Wang, and GenBank Accession Number AF117228 are considered to be analogous to the claimed invention because they are all in the same field of classification of HLA. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of determining an individual HLA expression pattern with primers or probes as taught in Willers to incorporate the use of exon-exon-boundary-spanning primers for HLA genes as taught in Wang and to incorporate the development and use of primer or probes according to GenBank Accession Number AF117228 because it is obvious to develop any primer or probe from a known gene sequence.
Regarding claim 28, Willers teaches the detection of mRNA expression of classical HLA genes (HLA-A and HLA-B) and of a non-classical HLA gene (HLA-G) (and comparison of the expression levels between the classical HLA genes (first HLA gene) and non-classical HLA gene (second HLA gene) (identifying a molecular subtype of the tumor) (pg. 1498 abstract lines 14-25; pg. 1499 column 1 1st full paragraph lines 1-5; pg. 1499-1500 paragraph bridging pg. 1499 & 1500 lines 11-12 & 36-39; pg. 1501 paragraph bridging column 1 & 2 lines 30-33; Table I).
Response to Arguments
The response traverses the rejection. The response asserts that independent claim 19 is amended to recite a method of determining individual HLA patterns of a tumor in a subject omitting reference to the production of a therapeutic and amended to specify that the second region (or both the first and second region) comprises use of exon-exon-boundary-spanning primers and that the cited references, alone or in combination, fail to teach or suggest a method having these features. Further, the response asserts while Willers may describe differential transcription of classical and nonclassical HLA genes in cancer cells, the reference lacks any teaching related to the use of exon-exon-boundary-spanning primers or comparing the results from boundary vs. non-boundary assays to infer HLA isoforms and instead, the assays disclosed in Willers employ intron-spanning primers. The response asserts that therefore neither Wolfgang (as evidenced by Carosella or Cereb) nor GenBank remedies this deficiency as GenBank is cited only as disclosing features of a dependent claim and Wolfgang is cited only providing a teaching to the production of a therapeutic which is not a feature of claim 19. This argument has been thoroughly reviewed but was not found persuasive. First, as discussed above, the instant specification, pg. 13, broadly teaches that determining HLA isoforms based on the comparison of the first and second expression levels encompasses if the expression level of a region encoding a portion of a first exon exceeds the expression level of a region encoding a portion of a second exon. Due to this, determining HLA isoforms based on the comparison of the first and second expression levels is interpreted to encompass the comparison of an expression levels of a region encoding a portion of a first exon and a portion of a second exon. Willers teaches the expression levels of the classical HLA-A and HLA-B genes are measured from the 3’ and 5’ untranslational (UT) region of the HLA-A and HLA-B gene segments which indicates no presence of an exon-exon boundary (first region comprises no exon-exon boundary) and the expression level of the non-classical HLA-G gene is measured from exon 3 to exon 5 which indicates the presence of an exon-exon boundary (the second region comprises an exon-exon boundary and primers span exon-exon with forward primer in one exon and reverse primer in another exon) (determining HLA isoforms based on comparing an expression level of a region comprising an exon-exon boundary to the expression of another region) (pg. 1499-1500 paragraph bridging pg. 1499 & pg. 1500 lines 4-12; Table I). Second, Wang, as discussed above and applied to newly amended claim 19 as necessitated by amendment, teaches a method of HLA typing a variety of HLA genes and their alleles through amplification and sequencing through PCR primers designed to capture multiple exons of different HLA genes (use of exon-exon-boundary-spanning primers), for example a primer for HLA-A and HLA-B designed to amplify from exon 1 to exon 7 (abstract lines 1-12; pg. 8677 column 1 1st full paragraph lines 1-7; Fig. 1). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of determining expression levels between a classical and non-classical HLA gene to determine an individual HLA expression pattern in Willers to incorporate the use of exon-exon-boundary-spanning primers for HLA genes as taught in Wang because Wang teaches that doing so would provide a high-resolution and cost-effective method for amplifying HLA genes and their many alleles.
The response also asserts that by extension, claims depending from claim 19 are non-obvious in view of the cited references. This argument has been thoroughly reviewed but was not found persuasive due to the reasons set forth above.
For these reasons, and the reasons already made of record and modified to address the claims as currently amended, the rejections are maintained and applied to the newly amended claims.
Conclusion
Claims 19, 21, 22, 24-26, 28, 30, & 32 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY C BUCHANAN whose telephone number is (703)756-1315. The examiner can normally be reached Monday-Friday 8:00am-5:00pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached at (571) 272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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