DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/19/2025 has been entered.
Claim Status
Claims 2, 4-13, 15-28, 30, 32-40, 52, and 55 have been cancelled and claims 1, 42, and 48 have been amended, as requested in the amendment filed on 11/19/2025. Following the amendment, claims 1, 3, 14, 29, 31, 41-51, and 53-54 are pending in the instant application.
Claims 1, 3, 14, 29, 31, 41-51, and 53-54 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1, 3, 14, 29, 31, 41-51, and 53-54 have an effective filing date of July 15, 2018 corresponding to PRO 62/698,185.
Claim Objections - Withdrawn
Claims 1, 42, and 48 were objected to because the claims had periods in the labels denoting steps (e.g., a., b., i., ii., etc.). Applicant has amended the claims such that the steps are now denoted as “a)”, “b)”, “i)”, “ii)”, etc. As such, the objection to claims 1, 42, and 48 is withdrawn.
Claims 1, 3, 48, 50, and 53 were objected to because they recited “expression of lysophosphatidic acid (LPA)” and/or measuring “expression” thereof. Applicant has amended claims 1, 3, 48, 50, and 53 to recite “LPA levels” instead of “LPA expression”. As such, the objection to claims 1, 3, 48, 50, and 53 is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 1, 3, and 29 were rejected under 35 U.S.C. 103 as being unpatentable over US 2010/0069256 A1 (herein after referred to as "Baribaud"; it is noted that the instant Office Action has corrected the citation to the Baribaud reference, which is a US PGPub not a WIPO document).
Claim 14 was rejected under 35 U.S.C. 103 as being unpatentable over US 2010/0069256 A1 (herein after referred to as "Baribaud") in further view of non-patent literature by Knowlden and Georas (J. Immunol., 2014, 192(3), 851-857; previously cited on PTO-892; herein after referred to as "Knowlden") and non-patent literature by Benesch et. al (Journal of Lipid Research, 2015, 56, 1134-1144; previously cited on PTO-892; herein after referred to as "Benesch").
Claims 31 and 41 were rejected under 35 U.S.C. 103 as being unpatentable over US 2010/0069256 A1 (herein after referred to as "Baribaud") in further view of non-patent literature by Park and Jeen (World J. Gastroenterol., May 2018, 24(17) 1868-1880; previously cited on PTO-892; herein after referred to as “Park”).
As detailed below, upon further reconsideration in view of Applicant’s arguments, the cited prior art, and the instant specification, claim 1 and subsequently dependent claims 3, 14, 29, 31, and 41 are considered to not be enabled. As such, the above-listed rejections of claims 1, 3, 14, 29, 31, and 41 under 35 U.S.C. 103 in view of Baribaud, Park, Knowlden, and/or Benesch are withdrawn.
Claim Rejections - 35 USC § 101 - New
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, 3, 14, 29, 31, 41-51, and 53-54 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature/a natural phenomenon) without significantly more. The claim(s) recite(s) a method for determining suitability of a subject suffering from inflammatory bowel disease to be treated with a therapeutic agent that reduces localized inflammation comprising providing a gut/peripheral blood sample; measuring at least one of (i) LPA levels, (ii) expression of at least one of SLC22A4, METTL9, AGPAT3, MBOAT2, ATX, and CREB1, (iii) at least one molecule that regulates LPA expression, or (iv) expression of ATX; determining suitability by comparing the measured level/expression of the above-listed molecules/proteins to a predetermined threshold (levels/expression in gut/peripheral blood samples from subjects suffering from inflammatory bowel disease that do not respond to said therapeutic agent); and (1) not administering any therapeutic agent to said subject not likely to respond or (2) administering said therapeutic agent to said subject likely to respond.
Thus, the claims are directed to the judicial exception of the levels of LPA and the expression of various naturally occurring proteins.
In outcome (1), this judicial exception is not integrated into a practical application because the claims recite only the detection or observation of a naturally occurring phenomenon/law of nature, which is data gathering to observe the naturally occurring phenomenon/law of nature without applying the data to a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite use of routine laboratory procedures (i.e., providing gut or peripheral blood samples and in said sample(s) “measuring LPA levels” or “measuring expression” of one of various recited proteins. The steps of measuring LPA levels and/or measuring protein expression, are considered known, routine steps and are typically taken by those in the field to perform testing of a sample and are not elements that are sufficient to amount to significantly more than the judicial exception (see MPEP 2106.05(d)). For example, US Patent Application Publication 2010/0069256 A1 demonstrates practicing routine measurement of expression levels of various proteins in both gut and blood samples. Routine data gathering in order to observe a natural phenomenon/natural principle does not add a meaningful limitation to the method as it would be routinely used by those of ordinary skill in the art in order to observe the natural phenomenon/natural principle, and it fails to narrow the scope of the claims such that others are not foreclosed from using the law of nature/natural phenomenon. Methods of detecting natural phenomenon preempt all practical uses of it as others must use/detect the natural phenomenon to apply it to any other correlations, diagnosis, prognosis, therapeutic response, monitoring, etc.
Similarly, in outcome (2), this judicial exception is not integrated into a practical application because the step of “administering said therapeutic agent that reduces localized inflammation to said subject likely to respond”, as recited in independent claims 1, 42, and 48, is simply appending well-understood, routine, conventional activity of treating inflammatory bowel disease. A treatment with a “therapeutic agent that reduces localized inflammation” is a treatment specified at a high level of generality. It is a limitation that is well-understood, routine, conventional activity in the field of treating inflammatory bowel disease and does not amount to significantly more than the judicial exception (see MPEP 2106.05(d)). Applying or using the judicial exception to effect a particular treatment is considered a practical application, however, in the instant claims, a “therapeutic agent that reduces localized inflammation” is not considered a particular treatment (see MPEP 2106.05(f)). Therefore, the judicial exception is not integrated into a practical application.
To obviate the rejection, there must be at least one additional element or physical step that applies, relies on, or uses the natural principle so that the claim amounts to significantly more than the judicial exception itself. The claimed method currently fails to provide a practical application of the judicial exception and fails to add any elements that amount to significantly more than the judicial exception.
Claim Rejections - 35 USC § 112 - New
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 1, 3, 14, 29, 31, and 41 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The Breadth of the Claims
Claim 1 is drawn to a method for determining suitability of a subject suffering from inflammatory bowel disease to be treated with a therapeutic agent that reduces localized inflammation comprising providing a gut/peripheral blood sample; measuring at least one of (i) LPA levels, (ii) expression of at least one of SLC22A4, METTL9, AGPAT3, MBOAT2, ATX, and CREB1, or (iii) at least one molecule that regulates LPA expression; determining suitability by comparing the measured level/expression of the above-listed molecules/proteins to a predetermined threshold (levels/expression in gut/peripheral blood samples from subjects suffering from inflammatory bowel disease that do not respond to said therapeutic agent); and administering said therapeutic agent to said subject likely to respond. More specifically, with regard to the expression of SLC22A4, expression of SCL22A4 above a predetermined threshold indicates the subject is likely to respond to treatment with said therapeutic agent and expression below said threshold indicates said subject is unlikely to respond to treatment with said therapeutic agent. Thus, with regard to SCL22A4, expression of SCL22A4 in a gut sample from a patient of the claimed method above the expression of SLC22A4 in gut samples from a subjects suffering from inflammatory bowel disease that do not respond to said therapeutic agent indicates a patient is likely to respond to treatment with said therapeutic agent. This method is not enabled in view of the prior art and the disclosure of the instant specification.
The State of the Prior Art/Level of Predictability in the Art
US 2010/0069256 A1 (herein after referred to as "Baribaud") teaches a method for assessment of the suitability of a target therapy for a gastrointestinal-related disorder in a subject that evaluates the presence, absence, and/or magnitude of expression of one or more genes in a 20- or 5-member gene panel in a sample wherein the method enables identification of the effectiveness of target therapies prior to starting a patient on such therapies (Abstract). The expression levels of genes are determined in different patient samples for which diagnosis information is desired, to provide expression profiles; normal tissue may be distinguished from lesion tissue and tissue from a treated patient may be distinguished from an untreated patient and by comparing expression profiles of tissue in different disease states that are known, information regarding which genes are important (including both up- and down-regulation of genes) in each of these states is obtained (Paragraph 0040). Baribaud further teaches the utility of response signature; the response signature for infliximab treatment in UC described can be assessed and used as described in Paragraphs 0110-0113 (utilized a colonic biopsy sample). The data according to the methods of Baribaud explicitly measured/compared SLC22A4 expression in gut samples in responders (R) versus non-responders (NR); the ratio for NR versus R is 2.3, indicating that NR have higher expression levels of SLC22A4 in gut samples, such that if NR were used as the reference standard, as required by instant claim 1, SLC22A4 expression in a patient sample below that of a NR would indicate treatment (see Page 13, Table 4; emphasis added). Thus, the data presented in Baribaud directly contradicts the method of instant claim 1 regarding SLC22A4 expression and the determination of treatment suitability.
It is further noted that Baribaud indicates the use of both gut tissue and peripheral blood samples (see Paragraph 0063). Additionally, Baribaud indicates that while evidence to support a role of TNFα in the pathogenesis of UC has been controversial, TNFα is found at increased levels in the blood, colonic tissue, and stools of UC patients (Paragraph 0003); thus expression profiles and response signatures associated with gut tissue samples and blood samples for the same condition would be expected to be similar. There is no evidence in the prior art to suggest that the correlation between an expression profile and therapeutic response would be different in a gut sample compared to a blood sample.
The Amount of Direction Provided by the Inventor/Existence of Working Examples
It is noted that the instant specification only provides data corresponding to blood samples (see Example 7, Figure 9A). No data is presented to support that a gut sample, from the same patient/patient subset, would have an expression profile/response signature opposite of that established in a blood sample.
Considering the breadth of the claims, the data established for SLC22A4 expression in cases of inflammatory bowel disease in the prior art, and the lack of working examples/direction provided by the inventor, claims 1, 3, 14, 29, 31, and 41 are considered to not be enabled.
Claim Rejections - 35 USC § 103 - Maintained
Claims 42-43, 45, and 47 stand as rejected under 35 U.S.C. 103 as being unpatentable over US 2010/0069256 A1 (herein after referred to as "Baribaud").
With regard to claim 42, Baribaud teaches a method for assessment of the suitability of a target therapy for a gastrointestinal-related disorder in a subject that evaluates the presence, absence, and/or magnitude of expression of one or more genes in a 20- or 5-member gene panel in a sample wherein the method enables identification of the effectiveness of target therapies prior to starting a patient on such therapies (Abstract). The expression levels of genes are determined in different patient samples for which diagnosis information is desired, to provide expression profiles; normal tissue may be distinguished from lesion tissue and tissue from a treated patient may be distinguished from an untreated patient and by comparing expression profiles of tissue in different disease states that are known, information regarding which genes are important (including both up- and down-regulation of genes) in each of these states is obtained (Paragraph 0040; emphasis added). The invention comprises a method of identifying subjects with UC and/or related diseases or disorders that are candidates for treatment with a particular therapeutic agent by evaluating their expression profile of one or more genes of the 20- or 5-gene panel (Paragraph 0011). In one embodiment, the UC-related gene profile is used to create an array-based method for prognostic or diagnostic purposes, the method comprising: (a) preparing a representative mixture of nucleic acids from a specimen obtained from a patient and causing said sample nucleic acids in the mixture to be labeled with a detectable marker; (b) contacting a sample with an array comprising a plurality of nucleic acid segments, wherein each nucleic acid segment is immobilized to a discrete and known address on a substrate surface wherein the panel of UC-related biomarkers is identified as a feature of the array by address, the array further comprises at least one calibration nucleic acid at a known address on the substrate, and contacting is performed under conditions in which a sample nucleic acid specifically may bind to the nucleic acid segment immobilized on the arrays; (c) performing a statistical comparison of all test samples from treated patients and a reference standard; and (d) comparing the pattern of intensity changes in features for the test sample to the pattern of intensity changes for those features which are members of the UC-related gene profile with historical patterns for samples taken from patients responsive to treatment with an anti-TNF antibody (Paragraphs 0012-0016). Fisher's Exact Test was used to select the top predictive probe sets distinguishing non-responders from responders within the 109 probe sets shown to be differentially expressed at Week 0; a subset of 20 probe sets classified non-responders and responders at Week 0 (Table 2) with an overall accuracy of 95.4% (21/22), sensitivity of 91.7% (11/12 responders) and specificity of 100% (10/10 non-responders) (Table 2) wherein genes involved in immune responses (IL-1β, TLR2, TREMl and LILRAl ), signal transduction (PDE4B, PBEFl and FCNl) or G-protein-coupled receptor protein signaling pathways (GPRl 09B, C5AR1 [C5Rl] and FPRLl) were represented (Paragraph 0108; emphasis added). Thus, Baribaud teaches how to determine/distinguish differentially regulated genes in a sample and how to elucidate predictive probe sets for use in methods of the invention. Baribaud further teaches the utility of the response signature; the response signature for infliximab treatment in UC described herein can be assessed and used as described as follows (Paragraphs 0110-0113):
1) Colonoscopic biopsy samples are obtained from lesional sites of patients with active UC (or Crohn's or related diseases and disorders). RNA will then be isolated from the biopsy samples and subjected to real time RT-PCR analysis. One microgram of total RNA in the volume of 50 μL is converted to cDNA in the presence of Multi Scribe Reverse Transcriptase. The reaction is carried out by incubating for 10 minutes at 25° C followed by 30 minutes at 48° C Reverse Transcriptase is inactivated at 95° C for 5 minutes. Twenty-five nanograms of cDNA per reaction are used in real time PCR with ABI 7900 system. In the presence of AmpliTaq Gold
DNA polymerase, the reaction is incubated for 2 minutes at 50° C. followed by 10 minutes at 95° C. Then the reaction is run for 40 cycles at 15 seconds, at 95° C. and 1 minute, 60° C per cycle using primer/probe sets specific for the genes in the response signature. Housekeeping genes, such as GAPDH or actin, will be used as internal calibrators. The relative change in gene expression is calculated using the delta-delta Ct method described by Applied Biosystems using values in the non-responder samples as the calibrator or comparator.
2) If a similar gene expression profile meets the parameters of the gene profile signature for a type of therapy, i.e., one or more of the 5 or 20 signature genes in the profiles described above show expression levels predictive of responders in relation to non-responders, the patient is considered a likely treatment responder to the therapy. In which case, the patient will be treated with the therapy.
3) If the gene expression profile does not meet the parameters of the gene profile signature for responder, i.e., lower expression level, then the patient is defined as a likely treatment non-responder. In which case, the patient may not be treated with the therapy. This enables a patient to avoid a type of therapy earlier after being deemed a non-responder. This can allow the patient to receive a different type of therapy.
The invention also provides a method for modulating or treating at least one gastrointestinal, immune related disease, in a cell, tissue, organ, animal, or patient including, but not limited to, at least one of gastric ulcer, inflammatory bowel disease, ulcerative colitis, Crohn's pathology, and the like (Paragraph 0088; emphasis added). Thus, Baribaud teaches a method of identifying subjects with UC and/or related diseases or disorders, wherein a related disease can include IBD, that are candidates for treatment with a particular therapeutic agent by evaluating their expression profile of one or more genes in a sample (e.g., colon biopsy [gut sample] or peripheral blood sample) and administering the therapeutic when appropriate wherein the target therapy is an anti-TNFα antibody (commonly used to treat localized inflammation) and the reference standard (i.e., predetermined threshold) is from an untreated ulcerative colitis patient, a responder to the target therapy, or a non-responder. More specifically, Baribaud discloses the measurement of SLC22A4 expression in responders (R) versus non-responders (NR); the ratio for NR versus R is 2.3, indicating that NR have higher expression levels of SLC22A4 such that if NR were used as the reference standard, SLC22A4 expression in a patient sample below that of a NR would indicate treatment. As such, while Baribaud does not disclose the exact method of instant claim 42, it is noted that the teachings of Baribaud discloses how to identify differentially expressed genes from a given sample, including up- and down-regulated genes and the use of different types of samples, how to identify predictive probe sets (to target/measure a set of differentially expressed genes of interest), and how to utilize such differentially expressed genes/probe sets in methods of the invention. Thus, the Baribaud reference reads on a method of determining suitability of a patient to be treated with, for example, infliximab wherein said method comprises: (i) providing a sample; (ii) measuring in said sample SLC22A4 expression, for example; (iii) comparing the measured expression of SLC22A4 to a predetermined threshold in order to determine suitability. Baribaud teaches that the samples of the method may be clinical samples, which include peripheral blood samples, and also indicates that the predetermined threshold may compare the sample to those of non-responders to treatment, wherein in the case of SLC22A4 it would be expected that SLC22A4 expression in a patient sample below that of a NR would indicate treatment.
Baribaud is considered to be analogous to the present invention as they are in the same field of methods for determining treatment suitability in cases of IBD, and as such it would have been obvious to one of ordinary skill in the art from the teachings of Baribaud reference to arrive at the method of instant claim 42 because combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success. Baribaud disclose how to identify differentially expressed genes from a given sample, including up- and down-regulated genes (e.g., SLC22A4) and the use of different types of samples (e.g., clinical samples that may include peripheral blood samples), how to identify predictive probe sets (to target/measure a set of differentially expressed genes of interest), and how to utilize such differentially expressed genes/probe sets in methods of the invention, and that said methods may be used to determine if a subject is likely to respond to treatment (e.g., infliximab treatment).
With regard to claim 43, Baribaud discloses the measurement of gene expression by measuring nucleic acids, as detailed above. It is specifically noted that Baribaud discloses that the term "nucleic acid" as used herein refers to a deoxyribonucleotide (DNA) or ribonucleotide (RNA) in either single- or double-stranded form and that the term encompasses nucleic acids containing known analogues of natural nucleotides and can be used interchangeably with gene, DNA, RNA, cDNA, mRNA, oligonucleotide primer, probe and amplification product. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 45 and 47, Baribaud teaches a therapeutic agent and its administration wherein the therapeutic agent is an anti-pro-inflammatory cytokine blocking antibody, more specifically an anti-TNFα antibody (e.g., infliximab), as detailed above. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Claims 46, 48-50, and 53 stand as rejected under 35 U.S.C. 103 as being unpatentable over US 2010/0069256 A1 (herein after referred to as "Baribaud") in further view of non-patent literature by Park and Jeen (World J. Gastroenterol., May 2018, 24(17) 1868-1880; previously cited on PTO-892; herein after referred to as “Park”).
With regard to claim 46, the method of claims 42 and 45 are rendered obvious by Baribaud. However, Baribaud does not teach or suggest the use of an anti-integrin antibody, or more specifically anti-ITGA4/B7 blocking antibody vedolizumab or anti-ITGB7 blocking antibody etrolizumab, as a therapeutic agent for treating/reducing localized inflammation. This deficiency is remedied by Park.
Park teaches that in inflammatory bowel disease (IBD), tumor necrosis factor plays an important role in mediating inflammation and several other pathways are also involved in eliciting an inflammatory response; leukocytes within the systemic circulation move to sites of inflammation, and blocking this pathway could be an important treatment strategy for IBD (Abstract). Park further teaches that anti-integrin therapy blocks the action of integrin on the surface of circulating immune cells and endothelial cell adhesion molecules, thereby inhibiting the interactions between leukocytes and intestinal blood vessels and currently, several anti-integrin drugs, including etrolizumab, which acts on β7-integrin, and PF-00547569, which targets mucosal addressin cell adhesion molecule-1, are undergoing clinical trials (Abstract). Anti-integrin agents inhibit the interactions between leukocytes and the intestinal vasculature, and selectively prevent the influx of inflammatory cells, which mediate the inflammatory process in IBD, into intestinal lesions (Page 1869, Column 1, Paragraph 2; emphasis added). The migration of leukocytes to the intestinal mucosa and the recruitment of immune cells to the site of inflammation due to increased expression of CAMs are essential to the development and maintenance of intestinal inflammation; leukocyte trafficking to the gut is central to the immunopathogenesis of IBD, and its inhibition is recognized as an important goal in the development of anti-IBD drugs (Page 1870, Column 2, Paragraph 3). Vedolizumab which acts selectively on the gut has shown few adverse events and is currently used in clinical practice; newer anti-integrin drugs that act on different integrins-related targets, such as AJM300, abrilumab, etrolizumab, and PF-00547659 have also been developed and are in clinical trials (Page 1868-1869, “Core Tip”). Park further teaches various phase II and phase III clinical trials wherein etrolizumab treatment had positive results and was demonstrated to be safe and tolerable (Page 1876-1877). Thus, Park teaches that anti-integrin antibodies, such as vedolizumab (anti-ITGA4/B7) and etrolizumab (anti-ITGB7) have shown success in IBD and their mechanism of action involves reducing localized inflammation by reducing the migration of leukocytes to the intestinal mucosa and the recruitment of immune cells to the site of inflammation.
Baribaud and Park are considered to be analogous to the present invention as they are in the same field of inflammation/inflammatory diseases and treatment of inflammation. Thus, it would have been obvious to one of ordinary skill in the art to modify the method of claims 1 and 42, rendered obvious by Baribaud, such that the therapeutic agent is an anti-integrin blocking antibody, such as those taught by Park, because the simple substitution of one known element for another (substitution of one anti-inflammatory agent for another) would be expected to yield predictable results.
With regard to claim 48, it is noted that Baribaud generally teaches the limitations of the instantly claimed methods drawn to a method of determining the suitability of a subject suffering from IBD for treatment with a therapeutic agent that reduces localized inflammation wherein the method may comprise: (i) providing a peripheral blood sample from the subject; (ii) measuring the expression of at least one molecule in the peripheral blood sample (e.g., SLC22A4, discussed above); (iii) determining the suitability of the subject for treatment with the therapeutic agent comprising comparing the expression of the at least one molecule in the sample to a predetermined threshold (i.e., expression in peripheral blood samples from subjects suffering from IBD that do not respond to the therapeutic agent); and (iv) administering said therapeutic agent to subjects likely to respond. It is noted that claim 48, however, specifies that from the peripheral blood sample a least one of (i) expression of LPA, (ii) expression of ATX, and/or (iii) expression of at least one molecule that regulates LPA expression are measured to determine suitability for treatment and that the therapeutic agent is either an anti-IGTA4/B7 or anti-ITGB7 blocking antibody. However, it is noted that, as detailed above, Baribaud discloses the measurement of SLC22A4 and its R vs NR expression ratio, which can be used to indicate treatment. SLC22A4, as indicated in the instant specification, is a known modulator of LPA expression and thus fits the definition of a molecule that regulates LPA expression. Additionally, as detailed above, Park provides motivation to utilize anti-integrin antibodies including vedolizumab and etrolizumab for the treatment of localized inflammation. As such, the combination of Baribaud and Park further render obvious instant claim 48.
With regard to claim 49, Park teaches that anti-integrin antibodies including vedolizumab (anti-ITGA4/B7) and etrolizumab (anti-ITGB7) are utilized to treat localized inflammation in IBD. Baribaud teaches the use of an anti-TNFα antibody to treat localized inflammation. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 50 and 53, Baribaud discloses the measurement of gene expression by measuring nucleic acids, as detailed above. It is specifically noted that Baribaud discloses that the term "nucleic acid" as used herein refers to a deoxyribonucleotide (DNA) or ribonucleotide (RNA) in either single- or double-stranded form and that the term encompasses nucleic acids containing known analogues of natural nucleotides and can be used interchangeably with gene, DNA, RNA, cDNA, mRNA, oligonucleotide primer, probe and amplification product. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Claim 44 stands as rejected under 35 U.S.C. 103 as being unpatentable over US 2010/0069256 A1 (herein after referred to as "Baribaud") in further view of non-patent literature by Knowlden and Georas (J. Immunol., 2014, 192(3), 851-857; previously cited on PTO-892; herein after referred to as "Knowlden") and non-patent literature by Benesch et. al (Journal of Lipid Research, 2015, 56, 1134-1144; previously cited on PTO-892; herein after referred to as "Benesch").
With regard to claim 46, the method of claim 42 is rendered obvious by Baribaud. However, Baribaud does not teach or suggest inducing a subject unsuitable to be treated with a therapeutic agent that reduces localized inflammation to be suitable to be treated with said therapeutic agent, by increasing LPA levels or activity. This deficiency is remedied by Knowlden and Benesch.
Knowlden teaches the relationship between ATX and LPA expression and their correlation with inflammation, as specified above, and also teaches that steady-state ATX is expressed by only a few tissues, including high-endothelial venules in lymph nodes, but inflammatory signals can up-regulate ATX expression in different tissues (Abstract). Knowlden teaches that LPA can be generated from lysophoshpatidylcholine (LPC) in blood by removal of the choline moiety by the enzyme lysophospholipase D (lyso-PLD) (Page 2, Paragraph 1) and that the dominant lyso-PLD in serum was found to be an enzyme known as autotaxin (ATX) (Page 2, Paragraph 2). Knowlden further teaches ATX expression and activity increase in different disease states, which suggests that the ATX/LPA axis may play a broader role in inflammation in general; for example, ATX is inducibly expressed on endothelial cells in the inflamed pancreas and in lung epithelial cells following bleomycin exposure, ATX expression is upregulated in synovial cells is from patients with rheumatoid arthritis and recent studies have firmly implicated ATX-derived LPA in the pathogenesis of inflammatory arthritis, while inhibition or genetic deletion of ATX significantly attenuated lung fibrosis (Pages 5-6). Thus, Knowlden teaches that the expression of ATX regulates LPA expression in the blood/tissues, wherein increased expression of ATX correlates to increased LPA expression and increased inflammation. As such, increased expression of LPA and/or ATX above a predetermined threshold is a positive indicator for treatment. It is also noted that increased expression of ATX and/or LPA correlate with increased inflammation, and as such stimulating the expression of ATX and/or LPA would induce inflammation which could then be treated by a therapeutic agent. Thus, Knowlden teaches the relationship between ATX and LPA expression and inflammation wherein ATX and LPA expression levels can be used as indicators for treatment in immune and inflammatory diseases.
Benesch teaches that ATX is a secreted enzyme, which converts extracellular lysophosphatidylcholine (LPC) into lysophosphatidate (LPA) and that ATX is produced in response to inflammation to mediate wound repair; if the inflammation is not resolved, then high ATX concentrations persist in association with inflammatory diseases such as arthritis and inflammatory bowel disease, wherein inflammatory bowel disease and hepatitis can progress to carcinogenesis in these organs as significantly increased ATX activity is associated with the growth of, for example, breast tumors and the ATX gene is among the top 40 most upregulated in metastatic cancer (Page 1134, Column 2). The authors disclose that both ATX and LPA levels increase in inflammatory conditions such as cancer; consistent with previous results, Balb/c mice with 4T1 breast tumors at day 21 have significantly elevated plasma ATX levels, the mice also have nearly twice the plasma LPA concentrations of control mice without cancer, and the mice also have nearly 40 times higher plasma levels of the pro-inflammatory cytokine, TNF-α (Page 1139, Column 2; Figure 7). The authors proposed that inflammatory cytokines counteract the inhibition of ATX mRNA expression by LPA and S1P; stimulation of SW-579 cells with TNF-α or IL-1β alone or in combination increased ATX mRNA concentrations wherein TNF-α or IL-1β also overcame the inhibition on ATX mRNA expression by either 1 μM LPA or S1P (Id.). Thus, Benesch established that addition of the pro-inflammatory cytokines, TNF-α and/or IL-1β, overcome LPA-mediated suppression of ATX expression; the production of inflammatory cytokines, such as TNF-α and/or IL-1β, in damaged and inflamed tissue is a signal for increased ATX expression and the need for LPA production to heal the wound, wherein if this process is successful and inflammation subsides, then LPA produced by ATX feeds back and blocks further ATX production but if inflammation is unresolved, then TNF-α and/or IL-1β stimulate further ATX production and the consequent formation of LPA stimulates further cytokine production in a vicious cycle (Page 1142, Column 1, Paragraphs 2-3; emphasis added). Thus, Benesch establishes that in inflammatory conditions, such as IBD and cancer, both ATX and TNF-α are elevated. Benesch further establishes that increased TNF-α correlated with increased ATX expression and subsequently increased LPA production, wherein TNF-α stimulates further ATX production and the consequent formation of LPA stimulates further cytokine production and inflammation is persistent and unresolved, suggesting that breaking the cycle with an ATX inhibitor, e.g., an anti-TNF-α antibody to reduce ATX expression, would be a potential way to control and reduce inflammation in inflammatory diseases (i.e., IBD) related to the ATX/LPA pathway.
Baribaud, Knowlden, and Benesch are considered to be analogous to the present invention as they are in the same field of inflammatory diseases and/or inflammation modulation. Thus, it would have been obvious to one of ordinary skill in the art to utilize the method of instant claim 42 rendered obvious by Baribaud in cases of IBD, wherein ATX and/or LPA expression levels or LPA regulatory molecules (e.g., SLC22A4) could be measured/used to determine suitability of a patient for treatment with a therapeutic agent to treat inflammation. Knowlden and Benesch teach the relationship between ATX/LPA expression and inflammatory conditions and their use as possible indicators for treatments. Increased LPA expression/activity, which one of ordinary skill in the art would recognize as being indicated by reduced expression of regulatory molecule SLC22A4, would thus indicate a subject is suitable for treatment; increasing LPA expression/activity would induce suitability of a patient for treatment that is otherwise unsuitable wherein, as suggested by the combination of Knowlden and Benesch, induction of inflammation by increased inflammatory cytokine levels/LPA production and subsequent control by disrupting the LPA/ATX axis can be an option for inflammation/IBD treatment. It would have been obvious to one of ordinary skill in the art to combine prior art reference teachings to arrive at the claimed invention with a reasonable expectation of success.
Claims 51 and 54 stand as rejected under 35 U.S.C. 103 as being unpatentable over US 2010/0069256 A1 (herein after referred to as "Baribaud") in further view of non-patent literature by Park and Jeen (World J. Gastroenterol., May 2018, 24(17) 1868-1880; previously cited on PTO-892; herein after referred to as “Park”), non-patent literature by Knowlden and Georas (J. Immunol., 2014, 192(3), 851-857; previously cited on PTO-892; herein after referred to as "Knowlden"), and non-patent literature by Benesch et. al (Journal of Lipid Research, 2015, 56, 1134-1144; previously cited on PTO-892; herein after referred to as "Benesch").
With regard to claims 51 and 54, the methods of claims 48 and 49 are rendered obvious by the combination of Baribaud and Park as detailed above. However, neither Baribaud nor Park disclose/suggest inducing a subject unsuitable for treatment to be suitable by increasing LPA levels or activity in the subject as Baribaud nor Park disclose any relationship between inflammation/IBD and LPA. This deficiency is remedied by Knowlden and Benesch.
Knowlden teaches the relationship between ATX and LPA expression and their correlation with inflammation, as specified above, and also teaches that steady-state ATX is expressed by only a few tissues, including high-endothelial venules in lymph nodes, but inflammatory signals can up-regulate ATX expression in different tissues (Abstract). Knowlden teaches that LPA can be generated from lysophoshpatidylcholine (LPC) in blood by removal of the choline moiety by the enzyme lysophospholipase D (lyso-PLD) (Page 2, Paragraph 1) and that the dominant lyso-PLD in serum was found to be an enzyme known as autotaxin (ATX) (Page 2, Paragraph 2). Knowlden further teaches ATX expression and activity increase in different disease states, which suggests that the ATX/LPA axis may play a broader role in inflammation in general; for example, ATX is inducibly expressed on endothelial cells in the inflamed pancreas and in lung epithelial cells following bleomycin exposure, ATX expression is upregulated in synovial cells is from patients with rheumatoid arthritis and recent studies have firmly implicated ATX-derived LPA in the pathogenesis of inflammatory arthritis, while inhibition or genetic deletion of ATX significantly attenuated lung fibrosis (Pages 5-6). Thus, Knowlden teaches that the expression of ATX regulates LPA expression in the blood/tissues, wherein increased expression of ATX correlates to increased LPA expression and increased inflammation. As such, increased expression of LPA and/or ATX above a predetermined threshold is a positive indicator for treatment. It is also noted that increased expression of ATX and/or LPA correlate with increased inflammation, and as such stimulating the expression of ATX and/or LPA would induce inflammation which could then be treated by a therapeutic agent. Thus, Knowlden teaches the relationship between ATX and LPA expression and inflammation wherein ATX and LPA expression levels can be used as indicators for treatment in immune and inflammatory diseases.
Benesch teaches that ATX is a secreted enzyme, which converts extracellular lysophosphatidylcholine (LPC) into lysophosphatidate (LPA) and that ATX is produced in response to inflammation to mediate wound repair; if the inflammation is not resolved, then high ATX concentrations persist in association with inflammatory diseases such as arthritis and inflammatory bowel disease, wherein inflammatory bowel disease and hepatitis can progress to carcinogenesis in these organs as significantly increased ATX activity is associated with the growth of, for example, breast tumors and the ATX gene is among the top 40 most upregulated in metastatic cancer (Page 1134, Column 2). The authors disclose that both ATX and LPA levels increase in inflammatory conditions such as cancer; consistent with previous results, Balb/c mice with 4T1 breast tumors at day 21 have significantly elevated plasma ATX levels, the mice also have nearly twice the plasma LPA concentrations of control mice without cancer, and the mice also have nearly 40 times higher plasma levels of the pro-inflammatory cytokine, TNF-α (Page 1139, Column 2; Figure 7). The authors proposed that inflammatory cytokines counteract the inhibition of ATX mRNA expression by LPA and S1P; stimulation of SW-579 cells with TNF-α or IL-1β alone or in combination increased ATX mRNA concentrations wherein TNF-α or IL-1β also overcame the inhibition on ATX mRNA expression by either 1 μM LPA or S1P (Id.). Thus, Benesch established that addition of the pro-inflammatory cytokines, TNF-α and/or IL-1β, overcome LPA-mediated suppression of ATX expression; the production of inflammatory cytokines, such as TNF-α and/or IL-1β, in damaged and inflamed tissue is a signal for increased ATX expression and the need for LPA production to heal the wound, wherein if this process is successful and inflammation subsides, then LPA produced by ATX feeds back and blocks further ATX production but if inflammation is unresolved, then TNF-α and/or IL-1β stimulate further ATX production and the consequent formation of LPA stimulates further cytokine production in a vicious cycle (Page 1142, Column 1, Paragraphs 2-3; emphasis added). Thus, Benesch establishes that in inflammatory conditions, such as IBD and cancer, both ATX and TNF-α are elevated. Benesch further establishes that increased TNF-α correlated with increased ATX expression and subsequently increased LPA production, wherein TNF-α stimulates further ATX production and the consequent formation of LPA stimulates further cytokine production and inflammation is persistent and unresolved, suggesting that breaking the cycle with an ATX inhibitor, e.g., an anti-TNF-α antibody to reduce ATX expression, would be a potential way to control and reduce inflammation in inflammatory diseases (i.e., IBD) related to the ATX/LPA pathway.
Baribaud, Park, Knowlden, and Benesch are considered to be analogous to the present invention as they are in the same field of inflammatory diseases and/or inflammation modulation. Thus, it would have been obvious to one of ordinary skill in the art to utilize the method of instant claims 48 and 49, rendered obvious by Baribaud and Park, in cases of IBD, wherein ATX and/or LPA expression levels or LPA regulatory molecules (e.g., SLC22A4) could be measured/used to determine suitability of a patient for treatment with a therapeutic agent to treat inflammation. Knowlden and Benesch teach the relationship between ATX/LPA expression and inflammatory conditions and their use as possible indicators for treatments. Increased LPA expression/activity, which one of ordinary skill in the art would recognize as being indicated by reduced expression of regulatory molecule SLC22A4, would thus indicate a subject is suitable for treatment; increasing LPA expression/activity would induce suitability of a patient for treatment that is otherwise unsuitable wherein, as suggested by the combination of Knowlden and Benesch, induction of inflammation by increased inflammatory cytokine levels/LPA production and subsequent control by disrupting the LPA/ATX axis can be an option for inflammation/IBD treatment. It would have been obvious to one of ordinary skill in the art to combine prior art reference teachings to arrive at the claimed invention with a reasonable expectation of success.
Response to Arguments
On Pages 10-13 of Remarks (11/19/2025), Applicant argues the following:
Baribaud teaches SLCC22A4 below a threshold as indicating treatment efficacy, while the instant application teaches that expression above a threshold indicates treatment. Baribaud is looking at the same disease, the same sample type and the same biomarker and is finding the exact opposite relationship. This is the epitome of teaching away from the instant claim. Baribaud may generally suggest looking for biomarkers of response, but with respect to the biomarker SLCC22A4, Baribaud is teaching that when it is low this means patient response, while the instant application is teaching that when it is high this means patient response.
The other biomarkers listed are all absent from Baribaud or any of the cited art; the cited art must teach each and every aspect of the claims. All of the other biomarkers are not taught and thus Baribaud does not teach each and every aspect of the claims.
Baribaud merely gives a plausible course of research that could be undertaken but does not actually render any of the listed biomarkers as obvious. This research course does not provide a few possible obvious alternatives but rather leaves open the possibility of a nearly infinite number of biomarkers. This does not render the instantly recited biomarkers as obvious.
Applicant’s arguments have been fully considered, but are deemed not persuasive.
Specifically with regard to Applicant’s “teaching away” argument, it is noted that claims 1, 3, 14, 29, 31, and 41 have been deemed as not being enabled absent evidence to the contrary. As such, the art rejection(s) based on the Baribaud reference have been withdrawn for claims 1, 3, 14, 29, 31, and 41, rending the argument moot. With respect to the maintained rejections of 41-51 and 53-54, with regard to the Baribaud reference it is noted that the method disclosed by Baribaud is still applicable to claims 41-51 and 53-54 as the reference explicitly discloses that both tissue (i.e., gut tissue) and blood (i.e., peripheral blood) samples may be utilized in the methods of the invention, wherein the method of Baribaud directly reads on the instant method as provided by the teachings already made of record. Briefly, it is noted that Baribaud teaches a method for assessment of the suitability of a target therapy for a gastrointestinal-related disorder in a subject that evaluates the presence, absence, and/or magnitude of expression of one or more genes in a 20- or 5-member gene panel in a sample wherein the method enables identification of the effectiveness of target therapies prior to starting a patient on such therapies (Abstract). The expression levels of genes are determined in different patient samples for which diagnosis information is desired, to provide expression profiles; normal tissue may be distinguished from lesion tissue and tissue from a treated patient may be distinguished from an untreated patient and by comparing expression profiles of tissue in different disease states that are known, information regarding which genes are important (including both up- and down-regulation of genes) in each of these states is obtained (Paragraph 0040). Baribaud further teaches the utility of response signature; the response signature for infliximab treatment in UC described can be assessed and used as described in Paragraphs 0110-0113 (utilized a colonic biopsy sample). The data according to the methods of Baribaud explicitly measured/compared SLC22A4 expression in gut samples in responders (R) versus non-responders (NR); the ratio for NR versus R is 2.3, indicating that NR have higher expression levels of SLC22A4 in gut samples, such that if NR were used as the reference standard, as required by instant claim 1, SLC22A4 expression in a patient sample below that of a NR would indicate treatment (see Page 13, Table 4; emphasis added). It is further noted that Baribaud indicates the use of both gut tissue and peripheral blood samples (see Paragraph 0063). Additionally, Baribaud indicates that while evidence to support a role of TNFα in the pathogenesis of UC has been controversial, TNFα is found at increased levels in the blood, colonic tissue, and stools of UC patients (Paragraph 0003); thus expression profiles and response signatures associated with gut tissue samples and blood samples for the same condition would be expected to be similar. As such, the method and data presented in Baribaud directly reads on using a peripheral blood sample, wherein it would be reasonably expected based, on the teachings and presented data of Baribaud, that SLC22A4 expression in a patient sample below that of a NR would indicate said patient is likely to respond to treatment with a therapeutic agent that reduces localized inflammation (e.g., infliximab, anti-TNFα antibody). Thus, Baribaud does not constitute a teaching away from claims 44, 46, 48-51, and 53-54.
With regard to Applicant’s argument that beyond SLC22A4, all other biomarkers listed are absent from Baribaud or any of the cited art and that as such the cited prior art does not teach each and every aspect of the claims, it is specifically noted that the independent claims recite “measuring in said sample at least one of…” in reference to the recited biomarkers. As such, under BRI, only one of the recited biomarkers is required to render the claims obvious, wherein Baribaud discloses SLC22A4, as applied to independent claim 42, and the additional reference Park is relied upon to establish a correlation between inflammatory bowel disease and the ATX/LPA axis, as applied to independent claim 48.
It is noted that no specific arguments regarding the combination of references as applied to reject claims 44, 46, 48-51, and 53-54 have been provided.
As such, in view of the above, the rejection of claims 41-51 and 53-54 under 35 U.S.C. in view of Baribaud, Park, Knowlden, and/or Benesch, as listed above, are deemed proper and are maintained.
Conclusion
Claims 1, 3, 14, 29, 31, 41-51, and 53-54 are pending. Claims 1, 3, 14, 29, 31, 41-51, and 53-54 are rejected. No claims are allowed.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/Laura B Goddard/Primary Examiner, Art Unit 1642