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 .
Claims Status
Claims 19, 21, 22, 24-26, 28, 30, & 32 filed on 07/01/2026 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 Claims 31, 33, & 34 are withdrawn from consideration as being drawn to a non-elected invention.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 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Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.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.
Response to Arguments
The response traverses the rejection. The response asserts that the streamlined analysis is appropriate because the eligibility of the claim, when viewed as a whole, is self-evident under 35 USC 101 and the analysis can end here and that the claims improve the technical field of cancer diagnostics and treatment. Further, the response asserts that independent claim 19 is not directly merely to a natural correlation or an abstract idea as the claim requires actually determining expression levels of RNA transcripts encoding regions of classical and non-classical HLA gens and determining HLA isoforms based on the comparison of those expression levels and therefore, these limitation require obtaining an actual sample, performing a molecular measurement of RNA transcript regions, and isoform determination for the resulting assay outputs and thus the claim as a whole provides technological improvements by virtue of well-defined method steps which does not seek to tie up any judicial exception such that others cannot practice it. This argument has been thoroughly reviewed but was not found persuasive as the claim as a whole providing technological improvements and providing method steps that do not seek to tie up any judicial exception such that others cannot practice it are not the standard for determining patent eligibility under 35 USC 101.
The response also asserts that no further analysis is needed but for the sake of argument the claims do not recite a judicial exception under Step 2A, Prong One and that the correlation between the expression levels of classical and non-classical HLA gene and the HLA pattern of a tumor is not being claimed and instead the claim recite a concrete in vitro molecular diagnostic method. Further, the response asserts that a human mind cannot determine an RNA transcript expression level of a tumor sample, let alone determine boundary-dependent HLA isoform information, without performing the recited laboratory measurement steps and therefore while the claims may arguably involve a judicial exception, they are not directed to one. This argument has been thoroughly reviewed but was not found persuasive. First, claim 19 recites determining HLA isoforms based on the comparison of the first and second expression levels and claim 24 recites wherein the comparing is further based on the determined expression levels to obtain the individual HLA pattern. Therefore, 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 as discussed further above. Second, 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 as the recitation of determining is broad and reads of data analysis steps that are recited with a high level of generality and could be practically performed in the human mind (See MPEP §2106.04(a)(III)(A)).
The response also asserts that, for the sake of argument only, an analysis of Step 2A, Prong Two is presented and that the claims recite additional elements that integrate the alleged judicial exception into a practical application in the claims as a whole. Further, the response asserts that the claims arguably recite a low of nature, however Applicant does not seek protection fore the correlation of expression levels of a classical and non-classical HLA gene and the HLA pattern of a tumor and instead the claimed methods apply a specific diagnostic workflow for determining individual HLA patterns of a tumor through comparison of RNA expression levels. Further, the response asserts that the specification also describe the practical laboratory implementation of this concept by RT-qPCR, including specific primer/probe sequences located across exon/exon boundaries and thus the claim uses a particular assay architecture to obtain isoform-resolving information from exon-exon boundary RNA transcripts and this is a meaningful technical limitation and not mere insignificant post-solution activity. This argument has been thoroughly reviewed but was not found persuasive as 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.
The response also asserts that claim 19 require the determined HLA isoforms to be reported to a clinical or patient and this reporting step is not an abstract “reading a report” divorced from the method and the reporting step communicates the determined HLA isoforms result generated by the claimed laboratory workflow to a clinical or patient and that reporting is part of a practical diagnostic use of the generated molecular information therefore applying the alleged correlation in a concrete diagnostic setting and not preempting all use of any natural relationship between HLA expression and tumor biology. This argument has been thoroughly reviewed but was not found persuasive for 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.
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 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
The response traverses the rejection. The response asserts that Willers does not disclose at least the claimed determination of HLA isoforms based on a comparison of the first and second expression levels, wherein one of the compared HLA regions comprises an exon-exon boundary and the other does not, or wherein both compared regions comprise exon-exon boundaries. Further, the response asserts that the intron-spanning primers of Willers, which are used to measure overall HLA-G expression, are different than the exon-exon-boundary-spanning primers of independent claim 19 as the present application explains an exon-exon-boundary is a region that “spans portions of two exons” such as a boundary between exon2/exon3, exon3/exon4, or exon4/exon5 and the disclosed RT-qPCR implementation employs RNA-specific primer/probe sequences located “across exon/exon boundaries” and thus the claimed boundary limitation is directed to the interrogation of an exon junction region and not merely using two primers located in different exons. Further, the response asserts that if anything Willers discloses an HLA-G amplicon generated using one primer in exon 3 and another primer in exon 5 and Willers does not disclose a primer or probe located across the exon3/exon4 or exon4/exon5 junction and does not disclose comparing boundary and non-boundary regions to determine HLA isoforms. Further, the response asserts that the Office’s interpretation effectively equates any RT-PCR amplicon extending from one exon to another with an “exon-exon-boundary” and this interpretation is unreasonable in view of the specification, which distinguishes a region that comprises an exon-exon-boundary from a region that comprises “no more than one exon” and further explains that HLA isoforms are determined from comparisons of expression levels of such defined regions. This argument has been thoroughly reviewed but was not found persuasive. First, the 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 discussion of exon-exon-boundary in the instant specification discusses “an exon-exon-boundary (i.e. span portions of two exons)” and “the group of exon-exon boundaries also includes boundaries formed by exon skipping, such exon 2 / exon 4 boundary etc.” in which exon-exon-boundary-spanning primers is given its broadest reasonable interpretation to encompass primers that span across two exons. Further, the claim as currently amended, does not require that a specific primer or probe is located across the exon/exon junction as the claim as currently amended recites “using exon-exon-boundary-spanning primers” (i.e. the primers span an exon/exon boundary).
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 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 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 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 the cited references, alone or in combination, fail to teach or suggest the claimed invention, as described above, Willers does not disclose the claimed exon-exon-boundary-based isoform determination and GenBank and Wang fail to remedy this deficiency. Further, the response asserts that Wang do not comprises exon-exon-boundaries and the primers of Wang are located entirely within an exon or at an exon-intron boundary and therefore a skilled artisan viewing Willers, GenBank, and Wang would have lacked any basis to derive the claimed invention. This argument has been thoroughly reviewed but was not found persuasive. First, the 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 discussion of exon-exon-boundary in the instant specification discusses “an exon-exon-boundary (i.e. span portions of two exons)” and “the group of exon-exon boundaries also includes boundaries formed by exon skipping, such exon 2 / exon 4 boundary etc.” in which exon-exon-boundary-spanning primers is given its broadest reasonable interpretation to encompass primers that span across two exons. Further, the claim as currently amended, does not require that a specific primer or probe is located across the exon/exon junction as the claim as currently amended recites “using exon-exon-boundary-spanning primers” (i.e. the primers span an exon/exon boundary). Further, Wang, as discussed above, also 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).
The response also asserts that for at least these reasons the claims 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.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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