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 .
The examiner reviewing your application at the PTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to examiner Jehanne Sitton.
Election/Restrictions
Applicant's election with traverse of Group I, species KCNJ10, JCNJ2, B2M, and HLA-B; expression and methylation, and mRNA in the reply filed on 3/9/2026 is acknowledged. The traversal is on the ground(s) that searching would not present a significant burden. This is not found persuasive because the application is a 371 application and is subject to unity of invention. In the instant situation, the groups lack unity of invention for the reasons made in the restriction requirement dated 1/7/2026. Regarding the traversal of the species election, it should be noted that the methods directed to diagnosing xerostomia by detecting expression and/or methylation of any of the genes in the tables listed in the claims lack unity of invention because each of the genes does not share the same or special technical feature. Each gene is structurally and functionally different and encodes structurally and functionally different proteins. These genes would be regarded as having the same or corresponding special technical feature if the alternatives had a common property and shared significant structural element that is essential to the common property or activity. In this situation, these structurally and functionally different genes do not share a significant structural element that is essential to the common property or activity of being associated with xerostomia. For example, the proteins encoded by the genes do not share any particular biological activity or active domain that is essential to being associated with xerostomia. As such, the genes in the tables, claimed in different combinations and subcombinations, in the alternative, lack unity of invention a priori.
The requirement is still deemed proper and is therefore made FINAL.
Claim status
Claims 1-19 are pending. Claims 3-7, 9, and 14-17 are withdrawn from consideration as being directed to non-elected inventions. Claims 1, 2, 8, 10-13, and 18-19 are examined herein as directed to the elected species of expression and methylation, mRNA, as well as the elected gene combination of KCNJ10, KCNJ2, HLA-B, and B2M.
Improper Markush Rejection
Claims 1, 2, 8, 10-13, 18, and 19 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements when the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. See MPEP § 2117 which provides guidance on the analysis of a proper Markush group.
Regarding claims 1, 2, 8, 10-13, 18, and 19, the Markush group in question is any alternatively recited combination comprising at least one gene of the 129 genes listed in the tables recited in the claims.
Regarding “single structural similarity”, the MPEP at 2117 IIA states that a recognized physical, chemical, or an art recognized class is a class where there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. It is specifically stated that “Thus a Markush grouping is ordinarily proper if all the members for the group belong to a recognized class (whether physical, chemical, or art recognized) and are disclosed in the specification to possess at least one property in common which is mainly responsible for their function in the claimed invention, and it is clear from their very nature or from the prior art that all members possess this property (emphasis added)”.
Therefore, in analysis of whether a claim contains an improper Markush grouping, the MPEP states: A Markush claim contains an “improper Markush grouping” if either (emphasis added): (1) the members of the Markush group do not share a ‘single structural similarity’ or (2) the members do not share a common use.”
In the instant case, the genes do not share any common structural element that is essential to the asserted utility of being associated with xerostomia. The different genes are from different parts of the human genome and are composed of different nucleic acid sequences encoding functionally different proteins.
Additionally, the prior art does not teach, nor is it clear from their nature, that all of the functionally different genes possess the property of being differentially expressed biomarkers associated with xerostomia.
For example:
The gene encoding KCNJ10 is located on chromosome 1. KCNJ10 is a potassium channel, primarily expressed in glial cells and renal distal tubes. Diseases associated with pathogenic variants include seizures, sensorineural deafness, ataxia, and Pendred syndrome.
The gene encoding HLA-B is on chromosome 6, and encodes a major histocompatibility complex Class I heavy chain. Diseases associated included spondyloarthropathy and Stevens-Johnson syndrome.
The gene encoding B2M is located on chromosome 15, and the protein is a serum protein. Diseases associated include hereditary systemic amyloidosis and immunodeficiency 43.
Therefore it is clear that when considering the different genes, even in different combinations, recited in the alternative in the rejected claims, there does not appear to be any common structure, domain, or function that is common for the genes individually, or any particular combination, let alone an association with xerostomia.
Furthermore, the recited alternative species in the groups set forth here do not share a single structural similarity, as each method relies on detection of different gene combinations. The only structural similarity present is that all the genes are made up of nucleotides. However, comprising nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide alone is not essential to the common activity of being correlated with subclinical acute rejection.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 2, 8, 10-13, 18, and 19 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 diagnosing and treating xerostomia, as well as monitoring treatment for xerostomia by detecting expression and/or DNA methylation of KCNJ10, KCNJ2, HLA-B, and B2M. This recitation is a natural correlation between expression levels of the genes, methylation levels of the genes, and xerostomia or xerostomia treatment response. 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 “diagnosing”, “monitoring”, and “comparing” which are abstract ideas because they encompass making observations and drawing conclusions and determinations which can occur entirely within the mind. It is therefore determined that the claims recite 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 detecting expression and/or methylation levels of combinations of genes, 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. Although claims 11 and 12 recite treatment, the administration steps in claims 11 and 12 are broadly recited (“xerostomia treatment”, “agent to treat or alleviate xerostomia”) such that they are merely a generalized “treat” limitation with no particularity that integrates the judicial exception into a practical application. These recitations are so general as to be mere instructions to apply the JE’s in a generic way. As such, these limitations have no more than a nominal relationship to the exceptions recited. The Supreme Court does acknowledge that it is possible to transform an unpatentable law of nature, but one must do more than simply state the law of nature while adding the words "apply it.” CLS BankInt’l, 134 S.Ct. at 2358; Prometheus, 132 S. Cl, at 1294.
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 step of isolating a biological sample is considered insignificant post solution activity. The steps of detecting expression and methylation levels 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)). Furthermore, the instant specification teaches that the expression levels were determined using Affymetrix arrays and the methylation levels were assessed with Illumina arrays that were available and used by practitioners in the field well before applicants effective filing date. 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 § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1, 2, 8, 10-13, 18, and 19 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The claims are rejected for being incomplete. The claims refer to a tables, however as set forth in the MPEP 2173.05(s):
Reference to Figures or Tables
Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
It is noted that the claims recite “wherein an increased or decreased level of expression and/or DNA methylation” of the at least one gene compared to the level of a reference identifies the subject as having xerostomia or response to treatment. However, without stating what the reference is, the metes and bounds of the claims are unclear because it is not clear how both increased or decreased expression or methylation of a gene are associated with xerostomia or treatment monitoring. The levels of expression and methylation for each gene are unclear in terms of whether they are increased, decreased, or both to diagnose xerostomia or monitor treatment of xerostomia.
The term “near” in claim 10 is indefinite because neither the claim nor the specification define the bounds of this ambiguous term. It is not clear where else in the genome or chromosome, a CpG cite would be considered “near” a particular gene.
The claims are replete with the use of “e.g.” as well as terms in parenthesis (unless defining an acronym), and quotations. These are indefinite because it is not clear if the limitations following “e.g.” or within the parenthesis or quotations are part of the claimed invention or merely exemplary and therefore not required.
Claims 12, 18, and 19 contain the trademark/trade names. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b). See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. The claims should be amended to remove the trademarks or tradenames.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, 8, 10, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Blochowiak (Blochowiak et al; Journal of Clinical Medicine, 2020; vol 9, pages 1-14) and Konsta (Konsta et al; BGIRSSO, vol 53, 2016, pages 1-10).
Blochowiak teaches analysis of the transcriptomic profile of genes in labial salivary glands involved in pathogenesis of SS (Sjogren’s Syndrome) related xerostomia using the Affymetrix U219 array (see abstract; whole document; pages 3-5). The Affymetrix U219 array necessarily contains probes for expression analysis of KCNJ10, KCNJ2, B2M, and HLA-B. Blochowiak teaches normalization to reference genes (comparing to a reference). Blochowiak does not teach analysis of DNA methylation of genes, however Konsta teaches analysis of epigenetic modifications in salivary glands of patients with SS using the Illumina Methylation 450 array which necessarily contains oligonucleotides for detecting CpG methylation of KCNJ10, KCNJ2, B2M, and HLA-B (see abstract; whole document; pages 2-3). Therefore it would have been prima facie obvious to the ordinary artisan prior to the effective filing date to have included methylation analysis as taught by Konsta, in the method of Blochowiak so as to provide a comprehensive analysis and identification of biomarkers associated with SS related xerostomia as taught by Blochowiak. It is noted that the only active steps required by the claims are isolating a biological sample which is biopsied parotid gland or saliva, detecting gene expression and methylation analysis of KCNJ10, KCNJ2, B2M, and HLA-B, and comparing the levels to a reference. The “wherein” clauses merely recite a necessary property of the levels detected, and do not distinguish the claims from the teachings of the prior art.
Claims 11-13, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Blochowiak and Konsta as applied to claims 1, 2, 8, 10, and 18 above, and further in view of Napenas (Napenas et al; Odontology, 2009, vol 97; pages 76-83).
The teachings of Blochowiak and Konsta are set forth above. Blochowiak and Konsta do not teach treatment of xerostomia or monitoring treatment of xerostomia, however Napenas teaches a review of xerostomia including available treatments (see table 3). Therefore it would have been prima facie obvious to the ordinary artisan prior to the effective filing date to have treated xerostomia, as taught by Napenas, in the patients taught by Blochowiak and Konsta. It would have additionally been prima facie obvious to have determined whether gene expression and methylation levels of particular biomarkers changed after treatment so as to provide potential biomarkers that could assess treatment efficacy. It is noted that the only active steps required by the claims are isolating a biological sample which is biopsied parotid gland or saliva, detecting gene expression and methylation analysis of KCNJ10, KCNJ2, B2M, and HLA-B, and comparing the levels to a reference. The “wherein” clauses merely recite a necessary property of the levels detected, and do not distinguish the claims from the teachings of the prior art.
Conclusion
No claims are allowed.
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/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
