DETAILED ACTION
Applicant’s response filed 10/09/2025 has been fully considered. The following rejections and/or objections are either reiterated or newly applied.
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 .
Claim Status
Claims 1-54, 56, 59-64, and 66-68 are cancelled by Applicant.
Claims 55, 57-58, 65, and 69 are currently pending.
Claim 65 was withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected invention Group II, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/03/2024.
Claims 55, 57-58 and 69 are herein under examination.
Claims 55, 57-58 and 69 are rejected.
Priority
The instant application claims domestic benefit as a continuation of U.S. Application No. 15/500,910 filed 01/31/2017, which claims domestic benefit to international application PCT/US15/45303 filed 08/14/2015, which claims domestic benefit to U.S. Provisional Patent Application No. 62/038,584 filed 08/18/2014, to U.S. Provisional Patent Application No. 62/104,032 filed 01/15/2015, and to U.S. Provisional Patent Application No. 62/179,175, filed 04/29/2015. The claims to the benefit of domestic priority for claims 55, 57-58 and 69 are acknowledged. As such, the effective filing date for claims 55, 57-58 and 69 is 08/18/2014.
Withdrawn Rejections
35 USC 103
The rejection of claims 55, 57-58 and 69 under 35 USC 103 as being unpatentable over Garcia et al. in view of Harkin and Law et al. is withdraw in view of a new ground of rejection, which has been applied as a result of further search and consideration of the claims.
Claim Rejections - 35 USC § 112
35 USC 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 55, 57-58 and 69 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
This rejection is newly applied based upon further search and consideration of the claims.
Claim 55 recites “measuring expression of one or more genes within the RNA; and calculating a ratio of M1 macrophages to M2 macrophages based on the measured gene expression”. The broadest reasonable interpretation of these limitations includes calculating the ratio using one gene. However, the specification does not disclose a single gene that can be used to determine a ratio between M1 and M2 macrophages. Rather, the specification discloses calculating an M1 to M2 ratio using at least one gene from M1 macrophages and at least one gene from M2 macrophages. As such, claim 55 is rejected for failing to comply with the written description requirement.
Claim 55 is rejected because it does not adequately describe a sufficient number of species for a claimed genus. MPEP 2163.II.A.3(a).ii recites that in order for a claimed genus to have a sufficient description of a representative number of species, wherein the genus has substantial variation of species within it, the disclosure must adequately describe a sufficient variety of species to reflect the variation within the genus. Claim 55 recites “measuring expression of one or more genes within the RNA; and calculating a ratio of M1 macrophages to M2 macrophages based on the measured gene expression”. Applicant claims the genus of any “one or more genes” whereas the disclosure of the instant application only discloses species of “one or more genes” specific to M1 and M2 macrophages. The species of the genus can be found, for example, on pg. 2 of the instant specification. However, the species of genes specific to M1 and M2 macrophages do not list a sufficient representative number of species for the claimed genus of any “one or more genes”. Therefore, the disclosure does not provide written description for any “one or more genes” specific to M1 and M2 macrophages.
Furthermore, claims 57-58 and 69 are also rejected because they depend on claim 55, which is rejected, and because they do not resolve the issue of indefiniteness.
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 55, 57-58 and 69 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and a natural phenomenon without significantly more.
This rejection is newly applied based upon further search and consideration of the claims.
Step 2A, Prong 1:
In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomena (Step 2A, Prong 1). In the instant application, claims 55, 57-58 and 69 recite a method. The instant claims recite the following limitations that equate to one or more categories of judicial exception:
Claim 55 recites “calculating a ratio of M1 macrophages to M2 macrophages based on the measured gene expression, wherein calculating the ratio of M1 macrophages to M2 macrophages comprises applying a linear sum method to weight the measured gene expression.”
Limitations reciting a mental process.
Above cited claim 55 is recited at such a high level of generality that it equates to a mental process because it is similar to the concepts of collecting information, analyzing it, and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), which the courts have identified as concepts that can be practically performed in the human mind. The broadest reasonable interpretation (BRI) of claim 55 in light of the specification includes performing calculations using the equation on specification pg. 32, lines 5-11. A human is capable of performing calculations using an equation.
Limitations reciting a mathematical concept.
Above cited claim 55 equates to a mathematical concept because it is similar to the concept of organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)), which the courts have identified as mathematical concepts. The BRI of claim 55 includes performing calculations using the equation on specification pg. 32, lines 5-11.
Limitations reciting a natural phenomenon.
Above cited claim 55 equates to a natural phenomenon because it is similar to the concept of a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk, Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017), which the courts have established as a natural phenomenon. Claim 55 uses gene expression from M1 and M2 macrophages to calculate a ratio of M1 to M2 macrophages.
As such, claims 55, 57-58 and 69 recite an abstract idea and a natural phenomenon (Step 2A, Prong 1: Yes).
Step 2A, Prong 2:
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). The judicial exception is not integrated into a practical application because the claims do not recite additional elements that reflect an improvement to a computer, technology, or technical field (MPEP § 2106.04(d)(1) and 2106.5(a)), require a particular treatment or prophylaxis for a disease or medical condition (MPEP § 2106.04(d)(2)), implement the recited judicial exception with a particular machine that is integral to the claim (MPEP § 2106.05(b)), effect a transformation or reduction of a particular article to a different state or thing (MPEP § 2106.05(c)), nor provide some other meaningful limitation (MPEP § 2106.05(e)). Rather, the claims include limitations that equate to insignificant extra-solution activity (MPEP § 2106.05(g)). The instant claims recite the following additional elements:
Claim 55 recites “extracting RNA from debrided wound tissue, wherein the debrided wound tissue was removed from a dressing previously applied to the wound; measuring expression of one or more genes within the RNA;”
Claim 57 recites “wherein the debrided wound tissue is from one or more selected from the group consisting of: a diabetic ulcer, a pressure ulcer, a chronic venous ulcer, a burn, a wound caused by an autoimmune disease, a wound caused by Crohn's disease, a wound caused by atherosclerosis, a tumor, a medical implant insertion point, a surgical wound, a bone fracture, a tissue tear, and a tissue rupture.”
Claim 58 recites “wherein the measuring expression step includes using one or more tools or techniques selected from the group consisting of: cDNA synthesis, quantitative PCR (qPCR), microarrays, and RNA Sequencing (RNA-seq).”
Claim 69 recites “wherein the method further comprises debriding wound tissue of a subject.”
Regarding the above cited limitations in claim 55 of extracting RNA and measuring gene expression from the RNA, these limitations equate to insignificant, extra-solution activity of necessary data gathering because they gather the gene expression data necessary to perform the judicial exception in claim 55 of calculating an M1 to M2 macrophage ratio (MPEP 2106.05(g)(3)).
Regarding the above cited limitations in claims 57-58, these limitations also equate to necessary data gathering because they further limit the debrided wound tissue and measured gene expression, which also recite necessary data gathering.
Regarding the above cited limitation in claim 69, this limitation equates to insignificant, extra-solution activity because it does not impose meaningful limits on the claim such that it is not nominally or tangentially related to the invention (MPEP 2106.05(g)(2)). Debriding wound tissue of a subject in claim 69 does not appear to have a functional role in relation to claim 55. Rather, wound tissue is debrided from the patient but no subsequent steps are recited for use of the patient’s debrided wound tissue.
As such, claims 55, 57-58 and 69 are directed to an abstract idea and a natural phenomenon (Step 2A, Prong 2: No).
Step 2B:
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). These claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because these claims recite additional elements that equate to well-understood, routine and conventional (WURC) limitations (MPEP § 2106.05(d)). The instant claims recite the following additional elements:
Claim 55 recites “extracting RNA from debrided wound tissue, wherein the debrided wound tissue was removed from a dressing previously applied to the wound; measuring expression of one or more genes within the RNA;”
Claim 57 recites “wherein the debrided wound tissue is from one or more selected from the group consisting of: a diabetic ulcer, a pressure ulcer, a chronic venous ulcer, a burn, a wound caused by an autoimmune disease, a wound caused by Crohn's disease, a wound caused by atherosclerosis, a tumor, a medical implant insertion point, a surgical wound, a bone fracture, a tissue tear, and a tissue rupture.”
Claim 58 recites “wherein the measuring expression step includes using one or more tools or techniques selected from the group consisting of: cDNA synthesis, quantitative PCR (qPCR), microarrays, and RNA Sequencing (RNA-seq).”
Claim 69 recites “wherein the method further comprises debriding wound tissue of a subject.”
Regarding the limitation in claim 55 of “wherein the debrided wound tissue was removed from a dressing previously applied to the wound”, this claim is being interpreted as a product-by-process. MPEP 2113.I recites “The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In the instant case, the “the debrided wound tissue” is the product and the process is “wherein the debrided wound tissue was removed from a dressing previously applied to the wound”. Thus, a reference that discloses extracting RNA from debrided wound tissue, wherein the debrided wound tissue was acquired through different means than from a dressing previously applied to the wound, will read on the limitation in claim 55 of “extracting RNA from debrided wound tissue, wherein the debrided wound tissue was removed from a dressing previously applied to the wound”.
The limitations in above cited claims 55, 57-58 and 69 equate to insignificant, extra-solution activity of necessary data gathering, as discussed above in Step 2A, Prong 2. Under Step 2B, limitations that equate to insignificant, extra-solution activity are evaluated for whether or not they are WURC (MPEP 2106.05(II)). These limitations equate to WURC limitations as discussed below by Jackson et al. (Jackson; Journal of tissue engineering and regenerative medicine 3, no. 2 (2009): 129-138; newly cited), Brem et al. (“Brem”; Molecular medicine 13, no. 1-2 (2007): 30-39; newly cited), and Derrick et al. (“Derrick”; International wound journal 5, no. 5 (2008): 615-624; newly cited).
Jackson teaches “Traumatically injured muscle was collected with Institutional Review Board (IRB) approval from the Walter Reed Army Medical Center (WRAMC). Patients were considered for inclusion in this study if they were exposed to orthopedic trauma and sustained extensive soft tissue extremity wounds … Tissue was collected at each debridement and irrigation until definitive closure of the wounds was attained” (pg. 130, col. 2, para. 2). Jackson teaches “The differentiated cells were lysed in TRIzol … and the RNA was extracted in the TRIzol according to the manufacturer’s protocol” (pg. 132, col. 1, para. 2). Jackson teaches “The RNA samples were reverse-transcribed with the SuperScript III System for qRT–PCR … The expression levels of osteogenic, adipogenic and chondrogenic genes were assayed by conventional PCR using Platinum Taq” (pg. 132, col. 1, para. 2).
Brem teaches molecular markers in patients with chronic wounds to guide surgical debridement (title). Brem teaches “We obtained biopsies from three patients at two locations, the nonhealing edge (prior to debridement) and the adjacent, nonulcerated skin of the venous ulcers (post debridement), and evaluated their histology, biological response to wounding (migration) and gene expression profile” (abstract). Brem also teaches “Chronic wound skin biopsies were obtained from discarded tissue after debridement procedures on three patients … whereas majority of the samples were stored in RNAlater (Ambion) for the subsequent RNA isolation … Total RNA was isolated using RNeasy (QIAGEN) following commercial protocol … Microarray Suite 5.0 (Affymetrix) was used for data extraction and for further analysis, data mining tool 3.0 (Affymetrix), and GeneSpring™ software 7.2 (Silicon Genetics) was used for normalization, fold change calculations, and clustering. Differential expressions of transcripts were determined by calculating the fold change” (pg. 31, col. 2-3).
Derrick teaches “one circular 3-cm diameter full-thickness wound was created on the mid-dorsum of each animal” (pg. 616, col. 2, last para. – pg. 617, col. 1, para. 1). Derrick teaches “At the conclusion of the experiment on day 2, wounded tissue was quickly removed and stored in RNAlater at 20C. Total RNA was isolated from tissue” (pg. 617, col. 2, para. 2). Derrick teaches “Gene expression profiles were generated … Each microarray contains approximately 28,000 features that include a set of about 1,000 controls. Each microarray uses 60-mer oligonucleotide probes (26, 857) designed against 27,088 genes covering 43,508 transcripts” (pg. 617, col. 2, para. 3).
When these additional elements are considered individually and in combination, they do not provide an inventive concept because they all equate to WURC limitations, as taught above by Jackson, Brem, and Derrick. Therefore, these additional elements do not transform the claimed judicial exception into a patent-eligible application of the judicial exception and do not amount to significantly more than the judicial exception itself (Step 2B: No).
As such, claims 55, 57-58 and 69 are not patent eligible.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 55, 57-58 and 69 are rejected under 35 U.S.C. 103 as being unpatentable over Garcia (“Garcia”; IDS Document; US 2012/0129186 A1, pg. 1-11, published 04/24/2012; previously cited) in view of Harkin (“Harkin”; WO 2012/167278 A1, pg. 1-92; published 06/12/2012; previously cited on PTO892 mailed 05/16/2024) and Klimcakova et al. (“Klimcakova”; Diabetologia 54, no. 4 (2011): 876-887; newly cited).
This rejection is newly applied based upon further search and consideration of the claims.
The bold and italicized text below are the limitations of the instant claims, and the italicized text serves to map the prior art onto the instant claims.
Claim 55:
A method of assessing a wound, the method comprising:
Garcia discloses a method/device for determining the healing phase of a wound by detecting specific biomarkers (abstract).
extracting RNA from debrided wound tissue, wherein the debrided wound tissue was removed from a dressing previously applied to the wound;
Garcia teaches biomarkers extracted from patient samples “from tissue which is either adhered to dressing material (upon removal of the dressing from the wound) or from non-necrotic tissue removed during debridement of the wound” [14] [31]. The non-necrotic tissue removed during debridement of a wound also equates to debrided wound tissue because the instant specification on pg. 19, lines 5-8, defines debrided wound tissue as “debrided tissue, which can include, but is not limited to, dead, damaged, or infected tissue.”
However, Garcia does not teach extracting RNA as a biomarker from the wound tissue.
Harkin discloses methods for identifying expression of biomarkers that are predictive for whether a cancer will be responsive or non-responsive to a therapeutic agent (abstract). Harkin teaches mRNA can be a biomarker [14] [55], isolating total RNA from diseased tissue [75], and quantifying gene expression from extracted mRNA [14] [50-51].
measuring expression of one or more genes within the RNA; and
Garcia teaches measuring biomarkers from patient tissue [35-36] [62] [65]. Garcia also teaches measuring biomarkers using PCR and quantitative real-time PCR [58].
However, Garcia does not teach measuring gene expression from extracted RNA.
Harkin teaches mRNA as a biomarker [14] [55], isolating total RNA from diseased tissue [75], and quantifying gene expression from mRNA [14] [50-51].
calculating a ratio of M1 macrophages to M2 macrophages based on the measured gene expression,
Garcia teaches calculating a ratio between M1 and M2 macrophages by using biomarkers specific to each cell type [44] [46]. Garcia teaches measuring biomarkers using PCR or qPCR [58].
However, Garcia does not teach calculating the ratio between M1 and M2 macrophages using measured gene expression from extracted RNA.
Harkin measures biomarkers such mRNA expression from diseased tissue using RT-qPCR for diagnostic and prognostic purposes [50] [75] [90] as well as calculating a ratio between two or more genes or their gene products [58]. Harkin discusses measuring biomarkers at difference stages of a disease [58].
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified the method of Garcia for calculating a ratio of M1 to M2 macrophages by using cell-specific biomarkers to determine a healing phase of a wound by using gene expression as a biomarker acquired from total isolated RNA extracted from a diseased tissue using RT-qPCR as taught by Harkin [75] [90]. The motivation for doing so is taught by Harkin who states that gene expression profiles can be used for diagnostic or prognostic purposes [50]. Harkin also states that gene expression can be used a surrogate for detecting a level of a corresponding protein in a biological sample [59].
One of ordinary skill in the art would have had a reasonable expectation of success for the combination because Garcia states that any desired biomarker can be measured [7] [11], wherein the biomarker is any measurable biological substance that indicates a normal or abnormal biological process often used for evaluation of pharmacologic responses to therapeutic interventions [36]. Harkin recites that their biomarkers are used to determine responsiveness to a therapeutic regime (abstract), and that measuring mRNA may be used as a surrogate for detection of the level of the corresponding protein in the biological sample [89]. Thus, the combination of Harkin and Garcia would cause Garcia to use M1 and M2 specific gene expression biomarkers to determine a wound healing phase. Garcia teaches the specific biomarkers for M1 and M2 macrophages [17] [44].
wherein calculating the ratio of M1 macrophages to M2 macrophages comprises applying a linear sum method to weight the measured gene expression.
As discussed above, the combination of Garcia and Harkin disclose calculating a ratio of M1 to M2 macrophages using M1 and M2 specific gene expression biomarkers.
However, neither Garcia nor Harkin teach applying a linear sum to weight the measured gene expression biomarkers, wherein the weighted sum of gene expression biomarkers is used to calculate the ratio.
Klimcakova identifies “a set of human adipose tissue macrophage (ATM)-specific markers and investigates whether their gene expression in subcutaneous adipose tissue (SAT) as well as in visceral adipose tissue (VAT) is related to obesity and to the occurrence of the metabolic syndrome” (abstract). mRNA expression of macrophage-specific genes was measured by reverse transcription and real-time qPCR. These macrophage-specific genes comprise 24 genes, wherein a mean centroid was calculated for the genes (pg. 878, col. 2, para. 2 – pg. 879, col. 1, para. 1). Klimcakova teaches “The mean centroid is a variable that represents weighted average of the 24 gene expression levels. The mean centroids were used to compare ATM marker gene expression between the groups and, also, to assess the correlations between the genes and physiological variables” (pg. 879, col. 1, para. 1). The weighted average is a linear sum.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified the combined method of Garcia and Harkin for calculating a ratio of M1 to M2 macrophages using cell-specific gene expression biomarkers by generating a weighted average of cell-specific gene expression biomarkers, as taught by Klimcakova. The combination would have resulted in a weighted average of gene expression biomarkers for both M1 and M2 macrophages. The motivation for doing so is taught by Klimcakova who teaches that the weighted average assesses correlations between the genes and physiological variables (pg. 879, col. 1, para. 1). This would be applied to Garcia by assessing correlations between gene expression biomarkers for M1 and M2 macrophages and the stage of wound healing. Furthermore, there is also a general motivation to use more than 1 cell-specific marker because the more cell-specific markers used the more likely that a gene signature of a specific cell-type is captured, as taught by Kimcakova (pg. 877, col. 2. para. 1).
One of ordinary skill in the art would have had a reasonable expectation of success to calculate two weighted averages of cell-specific gene expression biomarkers, one for M1 macrophages and one for M2 macrophages, because Klimcakova calculated a weighted average of adipose tissue macrophage specific gene expression. There would have been a reasonable expectation of success to further divide macrophage markers into M1 and M2 specific biomarkers using the M1 and M2 macrophage biomarkers described in Garcia. There also would have been a reasonable expectation of success to calculate a ratio between M1 and M2 macrophages using a weighted average of M1 biomarkers and a weighted average of M2 biomarkers because the weighted average represents gene expression, wherein the ratio of Garcia is calculated based on expression, and because Garcia permits use of multiple biomarkers per M1 and M2 macrophages when calculating the ratio [46-47].
Regarding claim 57, Garcia teaches that the wounds include diabetic foot ulcers, burns, pressure ulcers, venous stasis ulcers, and acute trauma which have no evidence of clinical infection [65].
Regarding claim 58, Garcia teaches measuring biomarker expression using Polymerase Chain Reaction PCR or Quantitative Real-Time PCR [58]. Klimcakova also measures mRNA expression using RT-qPCR (pg. 878, col. 2, para. 3).
Regarding claim 69, Garcia teaches that biomarkers are extracted from patient samples “from tissue which is either adhered to dressing material (upon removal of the dressing from the wound) or from non-necrotic tissue removed during debridement of the wound” [14] [31].
Response to Arguments under 35 USC 103
Applicant’s arguments filed 10/09/2025 have been considered but are not persuasive.
Applicant’s remarks regarding neither Garcia, Harkin, or Law providing a rationale or motivation or recognizing a need to calculate an M1 to M2 ratio by applying a linear sum to weight measured gene expression are not persuasive for the following reason (pg. 6, para. 4 of Applicant’s remarks). The new ground of rejection relies upon Klimcakova for calculating a weighted sum of gene expression for macrophages. Garcia teaches calculating a M1 to M2 ratio using cell-specific biomarkers. The combination of Garcia, Harkin and Klimcakova teach calculating a ratio of M1 to M2 macrophages using a weighted sum of gene expression. It is noted that Law is no longer an applied reference.
Applicant’s remarks regarding Harkin not teaching or suggesting calculating a M1 to M2 ratio by applying a linear sum to weight measured gene expression are not persuasive for the following reason (pg. 6, para. 6 – pg. 7, para. 1 of Applicant’s remarks). As discussed in the response above, it is the combination of Garcia, Harkin and Klimcakova that teach this limitation.
Applicant argues that one of ordinary skill would not use Harkin because Harkin is not related to macrophages and is directed toward cancer but not wound assessment (pg. 7, para. 2 of Applicant’s remarks). Applicant’s arguments are not persuasive for the following reasons:
Garcia and Harkin are both related to assessing biomarkers for diagnostic and prognostic purposes. Garcia discloses a wound diagnostic method using M1 and M2 macrophages to assess a wound healing phase (abstract) [35] [37] [44-45]. Garcia teaches that any combination of secreted biomarkers can be used to assess a wound healing phase [47-48]. Harkin discloses using a gene expression profile as a biomarker of a diseased tissue, which may be cancer, for diagnosis and prognosis [14] [50] [74]. Harkin also teaches that measured mRNA is a surrogate for levels of a corresponding protein in the biological sample [89]. When Harkin and Garcia are viewed together, they suggest that cell-specific gene expression biomarkers can be used for diagnostic or prognostic purposes.
Applicant’s arguments regarding Law have been considered but are not persuasive because Law is no longer applied (pg. 7, para. 2 – pg. 8, para. 1 of Applicant’s remarks).
Applicant’s arguments for not combining Garcia, Harkin, and Law are not persuasive for the same reasons discussed above (pg. 8, para. 2 of Applicant’s remarks). Specifically, Law is no longer applied and it is the combination of Garcia, Harkin, and Klimcakova that teach calculating an M1 to M2 macrophage ratio by applying a linear sum to weight the measured gene expression. As discussed above, Garcia and Harkin are related by using biomarkers for diagnostic and prognostic purposes.
In response to applicant's argument that there would not have been a reasonable expectation of success to derive a M1 to M2 ratio by applying a linear sum to weight measured gene expression because the Applicant found alleged surprising and unexpected results (pg. 9, para. 1 – pg. 10, para. 1 Applicants’ remarks), the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In other words, the combination of Garcia, Harkin, and Klimcakova teach calculating an M1 to M2 ratio by using a weighted average of macrophage-specific gene expression. The alleged unexpected results would have naturally flowed from this combination.
Applicant’s remarks regarding Law have been considered but are not persuasive because Law is no longer applied (pg. 11, para. 1 of Applicants’ remarks).
Conclusion
No claims are allowed.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Noah A. Auger whose telephone number is (703)756-4518. The examiner can normally be reached M-F 7:30-4:30 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Karlheinz Skowronek can be reached on (571) 272-9047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/N.A.A./Examiner, Art Unit 1687
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685