DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 December 24, 2025 has been entered.
3. Claims 1-19, 21-23 and 24-27 are pending.
Claims 7-12, 19, 21 and 22, drawn to non-elected species are withdrawn from examination.
Claims 1-6, 13-18 and 23-27 are examined on the merits to the extent it reads on species (site of alpha-5-beta-1 integrin detection): a. localized intracellularly away from three dimensional (3D) matrix adhesions in desmoplastic stroma isolated from a pancreas or kidney.
Maintained Grounds of Rejection
Claim Rejections - 35 USC § 103
4. 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.
5. 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.
6. The rejection of claim(s) 1-6, 24 and 25 under 35 U.S.C. 103 as being unpatentable over Clark et al. (Journal of Cell Science 118(2): 291-300, 15 January 2005), and further in view of Franco-Barraza et al. (abstract. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl): Abstract nr 1115) and Stokes et al. (Mol. Cancer. Ther. 10(11): 2135-2135, November 2011/ IDS reference #5 submitted February 27, 2020) is maintained.
Initial arguments make clear the requirements for the Office setting forth a proper prima facie case of obviousness, see Remarks submitted December 24, 2025, page 8, 3rd paragraph (para.). Applicant also asserts they are aware the rejection is based on a combination of references, however state they are not attacking references individually but “…instead pointing out the features of a reference that prevent the particular combination of references.”, see page 8, 2nd para.
Applicant argues secondary reference, Franco-Barraza teachings “…are opposite from the currently claimed invention and furthermore, one of ordinary skill in the art at the time of the invention would not have understood the findings disclosed in Franco-Barraza to have anything to do with being used as an indicator of treatment…Put another way, one of ordinary skill in the art at the time of the invention would have understood Franco-Barraza as teaching that (1) a5ß1-integrin activity is protective and tumor-suppressive (i.e., beneficial to the patient); (2) avß5-integrin inhibits α5ß1- integrin activity, thereby removing this protective effect; and (3) therefore, higher levels of α5ß1- integrin activity would be beneficial because it would counteract the tumor-promoting effects enabled by αvß5. Thus, one of ordinary skill at the time of the invention would not have been motivated to treat a patient showing elevated α5ß1-integrin levels, as such elevation would indicate a favorable, tumor-suppressive phenotype. Contrary to the findings in Franco-Barraza, Applicant currently claims and demonstrates in Example 4 that "80% of murine fibroblasts cultured in mD-ECM [murine desmoplastic-extracellular matrix] underwent myofibroblastic activation, with avB5 integrin inhibition significantly reducing this percentage (to 55%, P<0.0001). As in the human models, the phenotype was effectively rescued by the addition of a a5B1 integrin inhibitor (to -92% and -94% under a5B1 integrin inhibition alone or in combination with avB5 integrin inhibition, respectively) (see, FIGS. 3A and 3B) (paragraph [0152] of the published application. Again, put another way, the instant application shows that when the level of the active alpha-5-beta-1 integrin localized intracellularly away from three dimensional matrix adhesions is increased relative to the level of active alpha-5-beta-1 integrin localized intracellularly away from three dimensional matrix adhesions to a control is detrimental and therefore treatment is warranted. “Put simply, the instant application provides results and the claims are directed to a method that is opposite of what is reported in Franco-Barraza. Specifically, the instant application provides evidence that increased levels of active α5ß1-integrin and the localization of active α5ß1-integrin intracellularly away from the 3D matrix adhesions within the stroma of affected tissue is indicative of active desmoplasia, which is patient-detrimental, while high active a5ß1-integrin localized at 3D-adhesion structures represents the "protective" phenotype (e.g., see Examples 5 and 6 of the instant application). Thus, if one of ordinary skill in the art were to have followed the teachings of Franco-Barraza, one of ordinary skill in the art would have seen higher levels of active α5ß1-integrin and would have not been motivated to treat the subject.”, see page 10 of the Remarks.
Additionally, Applicant argues “Franco-Barraza is entirely silent regarding the location of active a5b1-integrin and is limited to only assessing levels of active α5ß1-integrin… even if one of ordinary skill in the art were to have followed the teachings of Franco- Barraza, one of ordinary skill in the art would have seen higher levels NOT where those levels were, of active α5ß1-integrin and would have not been motivated to treat the subject.”, see page 11, 1st para.
Applicant further argues “[l]ocalization of active alpha-5-beta-1 integrin intracellularly away from three dimensional matrix adhesions is a limitation NOT addressed in the Office Action nor Franco-Barraza. Localization is a novel and non-obvious limitation of the currently claimed invention. Applicant notes that Example 5 of the instant application shows that "3D-adhesions are highly dependent on α5ß1-integrin in N- ECM [normal]" (paragraph [0157] of the published application) and that "SNAKA51 is also a α5ß1- integrin stabilizing agent and treatment of cells grown in D-ECM reverted [to] adhesion phenotypes to those induced by N-ECM" (paragraph [0158] of the published application). These data demonstrate that this reversal occurred because α5ß1 translocated from pathological intracellular compartments to physiological extracellular plasma membrane locations, including 3D adhesions-not because total α5ß1 activation per se changed. Franco-Barraza, on the other hand was limited to measuring only total α5ß1 activity levels and misinterpreted such increases as evidence of protective function, while the instant application demonstrates that the spatial distribution of α5ß1 activity-not merely its total level-determines phenotype. This spatial redistribution mechanism was neither taught nor suggested by Franco-Barraza.”, see page 11, 2nd paragraph.
Applicant points out Examples 5 and 6 (spanning pages 36-46) stating they exemplify unexpected analysis of a5B1, which is indicative of whether or not treatment is required or not, given the spatial localization of active a5B1 integrin, see pages 11 and 12. But rather, “Franco-Barraza simply was not focused on not did it teach or suggest localization of active a5ß1-integrin as a mechanism and/or determination for treatment, but rather focused on only the detectable levels of active α5ß1-integrin as being the only indicator of a positive phenotype that would NOT have motivated one of ordinary skill in the art at the time of the invention to further treat a subject,”, see last 6 lines of page 12.
Applicant concludes arguments stating the combination of references fails to teach or suggest all the claimed elements, see pages 13 and 14.
Applicant’s arguments have been carefully reviewed and considered, but fail to persuade.
The SNAKA51 antibody of Clark is conformation dependent, thereby only able to bind a distinct conformation of a5B1 integrin. Hence, if there is active alpha-5-beta 1 integrin intracellularly away from the in vivo-mimetic 3D human stroma system taught by Franco-Barraza, the taught antibody will bind at that location and concomitantly identified. Utilizing the in vivo-mimetic 3D human stroma system of Franco-Barraza with the antibody of Clark one of ordinary skill in the art would be able to ascertain the spatial distribution of alpha-5-beta-1 activity.
Franco-Barraza provides the knowledge that “[a] discrete tuning of a5b1 integrin activity sustains the tumor-[extracellular matrix] ECM induced fibroblastic activation in pancreatic cancer stroma”, see title. It is clear to a person of ordinary skill in the art, this activity is not wanted and measures to induce a normal phenotype is the desired endpoint.
The information yielded from the detection of active alpha-5-beta 1 integrin, comparison of the integrin between the two different 3D adhesions (pancreatic stroma vs. normal stroma) provides information to one of ordinary skill in the art to move forward with treatment or not. It is art known alpha-5-beta-1 integrin participates in the activation of fibroblasts, “undergoing a desmoplastic (i.e. myofibroblastic phenotypic switch in response to tumor-associated (TA)…extracellular matrix (ECM).”, see 1st para. of Franco-Barraza abstract. “The desmoplastic microenvironment [is] characteristic of [pancreatic adenocarcinoma] PDAC [playing] a pivotal role in this aggressive cancer progression.”, see 1st para of Franco-Barraza. Therefore, one of ordinary skill in the art would be motivated to inhibit fibroblast activation with an effective therapeutic agent/regimen as taught by Stokes.
This modification of the primary reference in light of the secondary reference is proper because the applied references are so related that the appearance of features shown in one would suggest the application of those features to the other. See In re Rosen, 673 F.2d 388, 213 USPQ 347 (CCPA 1982); In re Carter, 673 F.2d 1378, 213 USPQ 625 (CCPA 1982), and In re Glavas, 230 F.2d 447, 109 USPQ 50 (CCPA 1956). Further, it is noted that case law has held that a designer skilled in the art is charged with knowledge of the related art; therefore, the combination of old elements, herein, would have been well within the level of ordinary skill. See In re Antle, 444 F.2d 1168,170 USPQ 285 (CCPA 1971) and In re Nalbandian, 661 F.2d 1214, 211 USPQ 782 (CCPA 1981). The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious.
Consequently, the combination of references does teach all the claim limitations. The rejection is maintained.
Clark teaches “…a conformation-dependent anti-α5 monoclonal antibody (SNAKA51) that converts α5β1 integrin into a ligand-competent form and promotes fibronectin binding”, see summary on page 291. This antibody is able to recognize “…a unique subpopulation of α5β1 integrins located in fibrillar adhesions that have a specific conformation recognized by a novel anti-α5 antibody”, see page 292, 1st column, 2nd paragraph. “The SNAKA51 antibody …identifies a unique subpopulation of α5β1 integrin compared with other anti-integrin antibodies”, see page 295, 1st sentence. The antibody of Clark will only specifically bind and recognize an active conformation of a5b1 that, which is uniquely expressed by active desmoplasia.
The SNAKA51 antibody taught by Clark specifically recognizes and binds “a unique subpopulation of α5β1 integrins located in fibrillar adhesions that have a specific conformation”, see page 289, 1st column, 2nd paragraph.
Clark does not teach the substrate for the SNAKA51 antibody is a three dimensional matrix adhesions in desmoplastic stroma isolated from a human pancreas or human kidney. Clark does not teach the desmoplastic stroma was isolated via biopsy, focal adhesion kinase activity was assessed and an individual was treated with a therapeutic regimen.
However, Franco-Barraza teaches an in vivo-mimetic 3D human stroma system, see 1st paragraph. “Using syngeneic human fibroblasts harvested from patient-matched normal and tumor samples, …a human 3D pancreatic stromal system” was produced, 2nd paragraph of Abstract. The harvested samples are regarded by the Examiner as surgical biopsies.
Moreover, Stokes teaches focal adhesion kinase (FAK) is activated and expressed in patient-derived pancreatic ductal adenocarcinoma (PDA) tumors and stromal components, see abstract. FAK can be detected via Western blotting, tissue staining and immunohistochemistry, see abstract; page 2136; and page 2137, Tissue…section and FAK/PYK2…sections with corresponding Figure 1 on page 2138.
Stokes also teaches administration of the small-molecule inhibitor, PF-562,271 to mice inhibited cancer-associated fibroblasts, as well as decreased tumor cell proliferation and growth, see PF-562,271…section beginning on page 2139; Figure 4 on page 2141 and Figure 5 on page 2142.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Clark, Franco-Barraza and Stokes to detect α5β1 integrin, as well as FAK in the desmoplastic 3D-adhesion structures of Franco-Barraza. The system taught by Franco-Barraza allows one of ordinary skill in the art “…to investigate the role of integrins during the [tumor-associated] TA-[extracellular matrix] ECM-induced phenotypic switch, focusing on two integrins associated with myofibroblastic differentiation, αvβ5 and α5β1.”, see 2nd paragraph. The systems taught by Franco-Barraza allow one of ordinary skill in the art to compare the two sets of adhesions and discern the levels of FAK activity.
Franco-Barraza’s “…findings correlate with clustering of α5β1integrin at TA-ECM-altered 3D adhesion structures, together with differences in α5β1 activation. Interestingly, we uncovered a mechanism whereby αvβ5-integrin activity, in a SFK/FAK-dependent manner, inhibits a FAK-independent α5β1-integrin activity, preventing it from inhibiting the TA-ECM-induced phenotypic switch. Finally, using patient samples, we verified our in vitro generated hypothesis, while results suggested that αvβ5-integrin inhibition may constitute a valid inhibitory PDAC-associated stroma clinical treatment/approach. Likewise, this work also concluded that the TA-ECM-regulated mechanism studied may comprise a clinically relevant occurrence, suggestive of a noteworthy value in assessing stromal activity in PDAC patients.”, see 3rd paragraph. Henceforth, one of ordinary skill in the art could utilize the information to understand the mechanistic functions of α5β1-integrin and FAK in this 3D matrix and utilize gleaned information and evidence from the Stokes’ mouse model to establish and implement a method of treating human pancreatic cancer with a therapeutic regimen such as PF-562,271.
Thus, the taught antibody is able to detect and determine the level of active α5β1integrin localized intracellularly away from 3D matrix adhesion structures taught in Franco-Barraza relative to the level of active α5β1integrin localized away from normal fibroblast-derived extracellular matrix (ECM) taught in Franco-Barraza, see entire Franco-Barraza abstract.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by the successful teachings in the references to assess and measure cancer biomarkers in an in vivo-like environment, such as the desmoplastic 3D-adhesion structures to determine clinical relevance of biomarkers such as α5β1 and FAK and an establish a predictive tumor model inclusive of different stages of tumorigenesis and assay probable clinical course(s) of treatment.
7. The rejection of claim(s) 1-6 and 23-25 under 35 U.S.C. 103 as being unpatentable over Clark et al. (Journal of Cell Science 118(2): 291-300, 15 January 2005), and further in view of Franco-Barraza et al. (abstract. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl): Abstract nr 1115), Stokes et al. (Mol. Cancer. Ther. 10(11): 2135-2135, November 2011/ IDS reference #5 submitted February 27, 2020) and Sherman MH, et al. (NIH Public Access Author Manuscript, pages 1-27, 2014 and published in final edited form, Cell. 159(1):80-93, Sep 25, 2014) is maintained.
Initial arguments make clear the requirements for the Office setting forth a proper prima facie case of obviousness, see Remarks submitted December 24, 2025, page 8, 3rd paragraph (para.). Applicant also asserts they are aware the rejection is based on a combination of references, however state they are not attacking references individually but “…instead pointing out the features of a reference that prevent the particular combination of references.”, see page 8, 2nd para.
Applicant argues secondary reference, Franco-Barraza teachings “…are opposite from the currently claimed invention and furthermore, one of ordinary skill in the art at the time of the invention would not have understood the findings disclosed in Franco-Barraza to have anything to do with being used as an indicator of treatment…Put another way, one of ordinary skill in the art at the time of the invention would have understood Franco-Barraza as teaching that (1) a5ß1-integrin activity is protective and tumor-suppressive (i.e., beneficial to the patient); (2) avß5-integrin inhibits α5ß1- integrin activity, thereby removing this protective effect; and (3) therefore, higher levels of α5ß1- integrin activity would be beneficial because it would counteract the tumor-promoting effects enabled by αvß5. Thus, one of ordinary skill at the time of the invention would not have been motivated to treat a patient showing elevated α5ß1-integrin levels, as such elevation would indicate a favorable, tumor-suppressive phenotype. Contrary to the findings in Franco-Barraza, Applicant currently claims and demonstrates in Example 4 that "80% of murine fibroblasts cultured in mD-ECM [murine desmoplastic-extracellular matrix] underwent myofibroblastic activation, with avB5 integrin inhibition significantly reducing this percentage (to 55%, P<0.0001). As in the human models, the phenotype was effectively rescued by the addition of a a5B1 integrin inhibitor (to -92% and -94% under a5B1 integrin inhibition alone or in combination with avB5 integrin inhibition, respectively) (see, FIGS. 3A and 3B) (paragraph [0152] of the published application. Again, put another way, the instant application shows that when the level of the active alpha-5-beta-1 integrin localized intracellularly away from three dimensional matrix adhesions is increased relative to the level of active alpha-5-beta-1 integrin localized intracellularly away from three dimensional matrix adhesions to a control is detrimental and therefore treatment is warranted. “Put simply, the instant application provides results and the claims are directed to a method that is opposite of what is reported in Franco-Barraza. Specifically, the instant application provides evidence that increased levels of active α5ß1-integrin and the localization of active α5ß1-integrin intracellularly away from the 3D matrix adhesions within the stroma of affected tissue is indicative of active desmoplasia, which is patient-detrimental, while high active a5ß1-integrin localized at 3D-adhesion structures represents the "protective" phenotype (e.g., see Examples 5 and 6 of the instant application). Thus, if one of ordinary skill in the art were to have followed the teachings of Franco-Barraza, one of ordinary skill in the art would have seen higher levels of active α5ß1-integrin and would have not been motivated to treat the subject.”, see page 10 of the Remarks.
Additionally, Applicant argues “Franco-Barraza is entirely silent regarding the location of active a5b1-integrin and is limited to only assessing levels of active α5ß1-integrin… even if one of ordinary skill in the art were to have followed the teachings of Franco- Barraza, one of ordinary skill in the art would have seen higher levels NOT where those levels were, of active α5ß1-integrin and would have not been motivated to treat the subject.”, see page 11, 1st para.
Applicant further argues “[l]ocalization of active alpha-5-beta-1 integrin intracellularly away from three dimensional matrix adhesions is a limitation NOT addressed in the Office Action nor Franco-Barraza. Localization is a novel and non-obvious limitation of the currently claimed invention. Applicant notes that Example 5 of the instant application shows that "3D-adhesions are highly dependent on α5ß1-integrin in N- ECM [normal]" (paragraph [0157] of the published application) and that "SNAKA51 is also a α5ß1- integrin stabilizing agent and treatment of cells grown in D-ECM reverted [to] adhesion phenotypes to those induced by N-ECM" (paragraph [0158] of the published application). These data demonstrate that this reversal occurred because α5ß1 translocated from pathological intracellular compartments to physiological extracellular plasma membrane locations, including 3D adhesions-not because total α5ß1 activation per se changed. Franco-Barraza, on the other hand was limited to measuring only total α5ß1 activity levels and misinterpreted such increases as evidence of protective function, while the instant application demonstrates that the spatial distribution of α5ß1 activity-not merely its total level-determines phenotype. This spatial redistribution mechanism was neither taught nor suggested by Franco-Barraza.”, see page 11, 2nd paragraph.
Applicant points out Examples 5 and 6 (spanning pages 36-46) stating they exemplify unexpected analysis of a5B1, which is indicative of whether or not treatment is required or not, given the spatial localization of active a5B1 integrin, see pages 11 and 12. But rather, “Franco-Barraza simply was not focused on not did it teach or suggest localization of active a5ß1-integrin as a mechanism and/or determination for treatment, but rather focused on only the detectable levels of active α5ß1-integrin as being the only indicator of a positive phenotype that would NOT have motivated one of ordinary skill in the art at the time of the invention to further treat a subject,”, see last 6 lines of page 12.
Applicant concludes arguments stating the combination of references fails to teach or suggest all the claimed elements, see pages 13 and 14. “Specifically, Clark, Franco-Barraza, and Stokes…, and Sherman fail to teach or suggest a method of inducing desmoplastic stroma to express a normal phenotype by "detecting the level of active alpha-5-beta-1 integrin localized intracellularly away from three dimensional matrix adhesions in desmoplastic stroma isolated from a pancreas or kidney of a human subject; comparing the level of the active alpha-5-beta-1 integrin localized intracellularly away from three dimensional matrix adhesions to the level of active alpha-5-beta-1 integrin localized intracellularly away from three dimensional matrix adhesions in normal stroma; and treating the human subject with a therapeutic regimen that inhibits fibroblast activation, the biologic activity of transforming growth factor (TGF) beta, or the biologic activity of alpha-5-beta-1 integrin in pancreatic stroma when the level of the active alpha-5-beta-1 integrin localized intracellularly away from three dimensional matrix adhesions is increased relative to the level of active alpha-5-beta-1 integrin localized intracellularly away from three dimensional matrix adhesions in normal stroma, thereby inducing the desmoplastic stroma to express a normal phenotype" (emphasis added)., page 13 and page 14, 1st para.
Applicant’s arguments have been carefully reviewed and considered, but fail to persuade.
The SNAKA51 antibody of Clark is conformation dependent, thereby only able to bind a distinct conformation of a5B1 integrin. Hence, if there is active alpha-5-beta 1 integrin intracellularly away from the in vivo-mimetic 3D human stroma system taught by Franco-Barraza, the taught antibody will bind and that location will be identified. Utilizing the in vivo-mimetic 3D human stroma system of Franco-Barraza with the antibody of Clark one of ordinary skill in the art would be able to ascertain the spatial distribution of alpha-5-beta-1 activity.
Franco-Barraza provides the knowledge that “[a] discrete tuning of a5b1 integrin activity sustains the tumor-[extracellular matrix] ECM induced fibroblastic activation in pancreatic cancer stroma”, see title. It is clear to a person of ordinary skill in the art, this activity is not wanted and measures to induce a normal phenotype is the desired endpoint.
The information yielded from the detection of active alpha-5-beta 1 integrin, comparison of the integrin between the two different 3D adhesions (pancreatic stroma vs. normal stroma) provides information to one of ordinary skill in the art to move forward with treatment or not. It is art known alpha-5-beta-1 integrin participates in the activation of fibroblasts, “undergoing a desmoplastic (i.e. myofibroblastic phenotypic switch in response to tumor-associated (TA)…extracellular matrix (ECM).”, see 1st para. of Franco-Barraza abstract. “The desmoplastic microenvironment [is] characteristic of [pancreatic adenocarcinoma] PDAC [playing] a pivotal role in this aggressive cancer progression.”, see 1st para of Franco-Barraza. Therefore, one of ordinary skill in the art would be motivated to inhibit fibroblast activation with an effective therapeutic agent/regimen as taught by Stokes.
Furthermore, the ability to assay FAK activity, known to contribute to migration of tumor cells, cancer-associated fibroblasts, and macrophages, impact survival rates, as well as elevated expression further allows assessment of 3D human stroma.
This modification of the primary reference in light of the secondary reference is proper because the applied references are so related that the appearance of features shown in one would suggest the application of those features to the other. See In re Rosen, 673 F.2d 388, 213 USPQ 347 (CCPA 1982); In re Carter, 673 F.2d 1378, 213 USPQ 625 (CCPA 1982), and In re Glavas, 230 F.2d 447, 109 USPQ 50 (CCPA 1956). Further, it is noted that case law has held that a designer skilled in the art is charged with knowledge of the related art; therefore, the combination of old elements, herein, would have been well within the level of ordinary skill. See In re Antle, 444 F.2d 1168,170 USPQ 285 (CCPA 1971) and In re Nalbandian, 661 F.2d 1214, 211 USPQ 782 (CCPA 1981). The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious.
Consequently, the combination of references does teach all the claim limitations. The rejection is maintained.
Clark teaches “…a conformation-dependent anti-α5 monoclonal antibody (SNAKA51) that converts α5β1 integrin into a ligand-competent form and promotes fibronectin binding”, see summary on page 291. This antibody is able to recognize “…a unique subpopulation of α5β1 integrins located in fibrillar adhesions that have a specific conformation recognized by a novel anti-α5 antibody”, see page 292, 1st column, 2nd paragraph. “The SNAKA51 antibody …identifies a unique subpopulation of α5β1 integrin compared with other anti-integrin antibodies”, see page 295, 1st sentence.
The SNAKA51 antibody taught by Clark specifically recognizes and binds “a unique subpopulation of α5β1 integrins located in fibrillar adhesions that have a specific conformation”, see page 289, 1st column, 2nd paragraph.
Clark does not teach the substrate for the SNAKA51 antibody is a three dimensional matrix adhesions in desmoplastic stroma isolated from a human pancreas or human kidney. Clark does not teach the desmoplastic stroma was isolated via biopsy, focal adhesion kinase activity was assessed and an individual was treated with a therapeutic regimen that comprises administering a vitamin D analog.
However, Franco-Barraza teaches an in vivo-mimetic three dimensional (3D) human stroma system, see 1st paragraph. “Using syngeneic human fibroblasts harvested from patient-matched normal and tumor samples, …a human 3D pancreatic stromal system” was produced, 2nd paragraph of Abstract. The harvested samples are regarded by the Examiner as surgical biopsies.
Moreover, Stokes teaches focal adhesion kinase (FAK) is activated and expressed in patient-derived pancreatic ductal adenocarcinoma (PDA) tumors and stromal components, see abstract. FAK can be detected via Western blotting, tissue staining and immunohistochemistry, see abstract; page 2136; and page 2137, Tissue…section and FAK/PYK2…sections with corresponding Figure 1 on page 2138.
Stokes also teaches administration of the small-molecule inhibitor, PF-562,271 to mice inhibited cancer-associated fibroblasts, as well as decreased tumor cell proliferation and growth, see PF-562,271…section beginning on page 2139; Figure 4 on page 2141 and Figure 5 on page 2142.
Sherman teaches “…calcipotriol (Cal), [is] a potent and nonhypercalcemic vitamin D analog to control [vitamin D receptor] VDR induction”, see page 4, VDR…section. “Cal-treated animal displayed attenuated inflammation and fibrosis, consistent with decreased [pancreatic stellate cells] PSCs (Figures S3A and S3B)” and decreased “[e]xpression of activation and cancer signatures genes… in isolated PSCs from mice treated with Cal compared to controls (Figure 3A)”, see page 5.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Clark, Franco-Barraza and Stokes to detect α5β1 integrin, as well as FAK in the desmoplastic 3D-adhesion structures of Franco-Barraza. The system taught by Franco-Barraza allows one of ordinary skill in the art “…to investigate the role of integrins during the [tumor-associated] TA-[extracellular matrix] ECM-induced phenotypic switch, focusing on two integrins associated with myofibroblastic differentiation, αvβ5 and α5β1.”, see 2nd paragraph. The systems taught by Franco-Barraza allow one of ordinary skill in the art to compare the two sets of adhesions and discern the levels of FAK activity.
Franco-Barraza’s “…findings correlate with clustering of a5β1-integrin at TA-ECM-altered 3D adhesion structures, together with differences in a5β1 activation. Interestingly, we uncovered a mechanism whereby αvβ5-integrin activity, in a SFK/FAK-dependent manner, inhibits a FAK-independent α5β1-integrin activity, preventing it from inhibiting the TA-ECM-induced phenotypic switch. Finally, using patient samples, we verified our in vitro generated hypothesis, while results suggested that αvβ5-integrin inhibition may constitute a valid inhibitory PDAC-associated stroma clinical treatment/approach. Likewise, this work also concluded that the TA-ECM-regulated mechanism studied may comprise a clinically relevant occurrence, suggestive of a noteworthy value in assessing stromal activity in PDAC patients.”, see 3rd paragraph. Henceforth, one of ordinary skill in the art could utilize the information to understand the mechanistic functions of α5β1-integrin and FAK in this 3D matrix and utilize gleaned information and evidence from the Stokes’ mouse model to establish and implement a method of treating human pancreatic cancer with a therapeutic regimen such as PF-562,271 (a small molecule inhibitor of FAK/PYK2), see Stokes abstract.
The antibody taught in Clark is able to detect and determine the level of active alpha-5-beta-1 integrin localized intracellularly away from 3D matrix adhesion structures taught in Franco-Barraza relative to the level of active alpha-5-beta-1 integrin localized away from normal fibroblast-derived extracellular matrix (ECM) taught in Franco-Barraza, see entire Franco-Barraza abstract.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by the successful teachings in the references to assess and measure cancer biomarkers in an in vivo-like environment, such as the desmoplastic 3D-adhesion structures to determine clinical relevance of biomarkers such as α5β1 and FAK and an establish a predictive tumor model inclusive of different stages of tumorigenesis and assay probable clinical course(s) of treatment.
Likewise, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Sherman with the pancreatic cancer treatment of Stokes because implementation of a vitamin D analog with pancreatic ductal adenocarcinoma (PDA) therapy has been shown to enhance said therapy, see title; and Summary on page 2.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by the successful teachings in Sherman, the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma”, as well as combinatorial treatment utilizing vitamin D therapeutic is able “..to reprise the quiescent state [of PSCs], resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone.”, see Summary on page 2; pages 5-7; KPC…segment on page 10; and Figures 5-7 spanning pages 25-27.
8. The rejection of claim(s) 13-18, 26 and 27 under 35 U.S.C. 103 as being unpatentable over Clark et al. (Journal of Cell Science 118(2): 291-300, 15 January 2005), and further in view of Franco-Barraza et al. (abstract. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl): Abstract nr 1115), Jiang et al. (Journal for ImmunoTherapy of Cancer 3(Suppl. 2: P400), published 4 November 2015/ IDS reference #3 submitted February 27, 2020) and Detjen et al. (Gut 49:251-262, 2001) is maintained.
Applicant initially states the what the Office Action sets forth, see Remarks submitted December 24, 2025, see segment C. beginning on page 14.
Applicant recites the teachings of secondary reference, Franco-Barraza and asserts the teachings “…are opposite from the currently claimed invention…one of ordinary skill in the art at the time of the invention would have understood Franco-Barraza as teaching that (1) a5ß1-integrin activity is protective and tumor-suppressive (i.e., beneficial to the patient); (2) avß5-integrin inhibits α5ß1- integrin activity, thereby removing this protective effect; and (3) therefore, higher levels of α5ß1-integrin activity would be beneficial because it would counteract the tumor-promoting effects enabled by αvß5. Thus, one of ordinary skill at the time of the invention would not have been motivated to treat a patient showing elevated α5ß1-integrin levels, as such elevation would indicate a favorable, tumor-suppressive phenotype.”, see paragraph bridging pages 15 and 16.
Applicant argues secondary reference, Franco-Barraza teachings “…are opposite from the currently claimed invention and furthermore, one of ordinary skill in the art at the time of the invention would not have understood the findings disclosed in Franco-Barraza to have anything to do with being used as an indicator of treatment…Put another way, one of ordinary skill in the art at the time of the invention would have understood Franco-Barraza as teaching that (1) a5ß1-integrin activity is protective and tumor-suppressive (i.e., beneficial to the patient); (2) avß5-integrin inhibits α5ß1- integrin activity, thereby removing this protective effect; and (3) therefore, higher levels of α5ß1- integrin activity would be beneficial because it would counteract the tumor-promoting effects enabled by αvß5. Thus, one of ordinary skill at the time of the invention would not have been motivated to treat a patient showing elevated α5ß1-integrin levels, as such elevation would indicate a favorable, tumor-suppressive phenotype. Contrary to the findings in Franco-Barraza, Applicant currently claims and demonstrates in Example 4 that "80% of murine fibroblasts cultured in mD-ECM [murine desmoplastic-extracellular matrix] underwent myofibroblastic activation, with avB5 integrin inhibition significantly reducing this percentage (to 55%, P<0.0001). As in the human models, the phenotype was effectively rescued by the addition of a a5B1 integrin inhibitor (to -92% and -94% under a5B1 integrin inhibition alone or in combination with avB5 integrin inhibition, respectively) (see, FIGS. 3A and 3B) (paragraph [0152] of the published application. Again, put another way, the instant application shows that when the level of the active alpha-5-beta-1 integrin localized intracellularly away from three dimensional matrix adhesions is increased relative to the level of active alpha-5-beta-1 integrin localized intracellularly away from three dimensional matrix adhesions to a control is detrimental and therefore treatment is warranted. “Put simply, the instant application provides results and the claims are directed to a method that is opposite of what is reported in Franco-Barraza. Specifically, the instant application provides evidence that increased levels of active α5ß1-integrin and the localization of active α5ß1-integrin intracellularly away from the 3D matrix adhesions within the stroma of affected tissue is indicative of active desmoplasia, which is patient-detrimental, while high active a5ß1-integrin localized at 3D-adhesion structures represents the "protective" phenotype (e.g., see Examples 5 and 6 of the instant application). Thus, if one of ordinary skill in the art were to have followed the teachings of Franco-Barraza, one of ordinary skill in the art would have seen higher levels of active α5ß1-integrin and would have not been motivated to treat the subject.”, see pages 15 and 16 of the Remarks.
Applicant argues “Franco-Barraza is entirely silent regarding the location of active a5b1-integrin and is limited to only assessing levels of active α5ß1-integrin… even if one of ordinary skill in the art were to have followed the teachings of Franco-Barraza, one of ordinary skill in the art would have seen higher levels NOT where those levels were, of active α5ß1-integrin and would have not been motivated to treat the subject.”, see page 16, 1st full para.
Applicant points out Examples 4-6 (spanning pages 34-46) stating “the phenotype was effectively rescued by the addition of [an] a5B1 integrin inhibitor”, unexpectedly showed higher levels of activated a5B1 in cells grown in D-ECM versus N-ECM” and “…both levels and localization of a5B1-integrin…is clinically prognostic for pancreatic cancer and renal cell carcinoma”, respectively, see pages 15-17.
Applicant continue arguments based on these Examples, “increases in a5B1 integrin activity induced in response to D-ECMs effectively established intracellular pools of integrin activity (FIG. 4H),” and “D-ECM induces increases in active pools (but not expression) of [an] a5B1 integrin”, see page 17, 1st full para. and page 18, 1st full para.
Applicant concludes arguments stating the combination of references fails to teach or suggest all the claimed elements, see pages 18-20. Stating “[i]n sum, Franco-Barraza simply was not focused on not did it teach or suggest localization of active a5ß1-integrin as a mechanism and/or determination for treatment, but rather focused on only the detectable levels of active α5ß1-integrin as being the only indicator of a positive phenotype that would NOT have motivated one of ordinary skill in the art at the time of the invention to further treat a subject,”, see page 18, 1st full para.
“Applicant submits that the combination of Clark, Franco-Barraza, Jiang, and Detjen fail to teach or suggest all of the claimed elements of claim 13, from which claims 14-18, 26 and 27 depend therefrom.”, see last six lines on page 18. As such, Applicant states “[n]othing in…Clark, Franco-Barraza, Jiang, and Detjen can fill the deficiencies left by Franco-Barraza.”, see para. bridging pages 19 and 20.
Applicant’s arguments have been carefully reviewed and considered, but fail to persuade.
The SNAKA51 antibody of Clark is conformation dependent, thereby only able to bind a distinct conformation of a5B1 integrin. Hence, if there is active alpha-5-beta 1 integrin intracellularly away from the in vivo-mimetic 3D human stroma system taught by Franco-Barraza, the taught antibody will bind and that location will be identified. Utilizing the in vivo-mimetic 3D human stroma system of Franco-Barraza with the antibody of Clark one of ordinary skill in the art would be able to ascertain the spatial distribution of alpha-5-beta-1 activity.
Franco-Barraza provides the knowledge that “[a] discrete tuning of a5b1 integrin activity sustains the tumor-[extracellular matrix] ECM induced fibroblastic activation in pancreatic cancer stroma”, see title. It is clear to a person of ordinary skill in the art, this activity is not wanted and measures to induce a normal phenotype is the desired endpoint.
The information yielded from the detection of active alpha-5-beta 1 integrin, comparison of the integrin between the two different 3D adhesions provides information to one of ordinary skill in the art to move forward with treatment or not. It is art known alpha-5-beta-1 integrin participates in the activation of fibroblasts, “undergoing a desmoplastic (i.e. myofibroblastic phenotypic switch in response to tumor-associated (TA)…extracellular matrix (ECM).”, see 1st para. of Franco-Barraza abstract. “The desmoplastic microenvironment [is] characteristic of [pancreatic adenocarcinoma] PDAC [playing] a pivotal role in this aggressive cancer progression.”, see 1st para of Franco-Barraza. Therefore, one of ordinary skill in the art would be motivated to inhibit fibroblast activation with an effective therapeutic agent/regimen as taught by Jiang. One of ordinary skill in the art is able to assay FAK activity, known to contribute to migration of tumor cells, cancer-associated fibroblasts, and macrophages, impact survival rates, as well as elevated expression further allows assessment of 3D human stroma, see Jiang. Both, Jiang and Detjen provide teachings of therapeutic agents for pancreatic cancer and in particular, those art known to inhibit fibroblast activation.
This modification of the primary reference in light of the secondary reference is proper because the applied references are so related that the appearance of features shown in one would suggest the application of those features to the other. See In re Rosen, 673 F.2d 388, 213 USPQ 347 (CCPA 1982); In re Carter, 673 F.2d 1378, 213 USPQ 625 (CCPA 1982), and In re Glavas, 230 F.2d 447, 109 USPQ 50 (CCPA 1956). Further, it is noted that case law has held that a designer skilled in the art is charged with knowledge of the related art; therefore, the combination of old elements, herein, would have been well within the level of ordinary skill. See In re Antle, 444 F.2d 1168,170 USPQ 285 (CCPA 1971) and In re Nalbandian, 661 F.2d 1214, 211 USPQ 782 (CCPA 1981). The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious.
Consequently, the combination of references does teach all the claim limitations. The rejection is maintained.
Clark teaches “…a conformation-dependent anti-α5 monoclonal antibody (SNAKA51) that converts α5β1 integrin into a ligand-competent form and promotes fibronectin binding”, see summary on page 291. This antibody is able to recognize “…a unique subpopulation of α5β1 integrins located in fibrillar adhesions that have a specific conformation recognized by a novel anti-α5 antibody”, see page 292, 1st column, 2nd paragraph. “The SNAKA51 antibody …identifies a unique subpopulation of a5β1 integrin compared with other anti-integrin antibodies”, see page 295, 1st sentence.
The SNAKA51 antibody taught by Clark specifically recognizes and binds “a unique subpopulation of α5β1 integrins located in fibrillar adhesions that have a specific conformation”, see page 289, 1st column, 2nd paragraph. The antibody of Clark will only specifically bind and recognize an active conformation of a5b1 that, which is uniquely expressed by active desmoplasia.
Clark teaches “…a conformation-dependent anti-α5 monoclonal antibody (SNAKA51) that converts α5β1 integrin into a ligand-competent form and promotes fibronectin binding”, see summary on page 291. This antibody is able to recognize “…a unique subpopulation of a5β1 integrins located in fibrillar adhesions that have a specific conformation recognized by a novel anti-α5 antibody”, see page 292, 1st column, 2nd paragraph. “The SNAKA51 antibody …identifies a unique subpopulation of α5β1 integrin compared with other anti-integrin antibodies”, see page 295, 1st sentence.
The SNAKA51 antibody taught by Clark specifically recognizes and binds “a unique subpopulation of α5β1 integrins located in fibrillar adhesions that have a specific conformation”, see page 289, 1st column, 2nd paragraph.
Clark does not teach the substrate for the SNAKA51 antibody is a 3D matrix adhesions in desmoplastic stroma isolated from a human pancreas or human kidney. Clark does not teach the desmoplastic stroma was isolated via biopsy and an individual was treated with a therapeutic regimen including interferon gamma and an antibody that binds to PD-1 or PD-L1.
However, Franco-Barraza teaches an in vivo-mimetic 3D human stroma system, see 1st paragraph. “Using syngeneic human fibroblasts harvested from patient-matched normal and tumor samples, …a human 3D pancreatic stromal system” was produced, 2nd paragraph of Abstract. The harvested samples are regarded by the Examiner as surgical biopsies.
Moreover, Jiang teaches FAK activity was detected and found elevated in human pancreatic ductal adenocarcinoma (PDAC), see page 1, bridging paragraph. It is art known that enhance FAK activity plays a role in the activation of fibroblast. Jiang also teaches administration of oral FAK kinase inhibitor VS-4718 doubles the rate of survival in a PDAC mouse model (KPC mice) and inhibits tumor progression, see page 1, 1st column. Hence, thereby inhibiting fibroblast activation. Jiang also teaches “VS-4718 significantly potentiated the efficacy of anti-PD-1 and anti-CTLA4 antibodies in KPC mouse models…”, see page 1, 2nd column full paragraph.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Clark, Franco-Barraza and Jiang to detect a5β1 integrin, as well as FAK in the desmoplastic 3D-adhesion structures of Franco-Barraza. The system taught by Franco-Barraza allows one of ordinary skill in the art “…to investigate the role of integrins during the [tumor-associated] TA-[extracellular matrix] ECM-induced phenotypic switch, focusing on two integrins associated with myofibroblastic differentiation, αvβ5 and a5β1.”, see 2nd paragraph. The systems taught by Franco-Barraza allow one of ordinary skill in the art to compare the two sets of adhesions and discern the levels of FAK activity.
Franco-Barraza’s “…findings correlate with clustering of a5β1-integrin at TA-ECM-altered 3D adhesion structures, together with differences in a5β1 activation. Interestingly, we uncovered a mechanism whereby αvβ5-integrin activity, in a SFK/FAK-dependent manner, inhibits a FAK-independent a5β1-integrin activity, preventing it from inhibiting the TA-ECM-induced phenotypic switch. Finally, using patient samples, we verified our in vitro generated hypothesis, while results suggested that αvβ5-integrin inhibition may constitute a valid inhibitory PDAC-associated stroma clinical treatment/approach. Likewise, this work also concluded that the TA-ECM-regulated mechanism studied may comprise a clinically relevant occurrence, suggestive of a noteworthy value in assessing stromal activity in PDAC patients.”, see 3rd paragraph. Henceforth, one of ordinary skill in the art could utilize the information to understand the mechanistic functions of α5β1-integrin and FAK in this 3D matrix and utilize gleaned information and evidence from the Stokes’ mouse model to establish and implement a method of treating human pancreatic cancer with a therapeutic regimen such as VS-4718 with a PD-1 or PD-L1 antibody.
Hence, the taught antibody is able to detect and determine the level of active a5β1 integrin localized intracellularly away from 3D matrix adhesions taught in Franco-Barraza relative to the level of active α5β1 integrin localized away from 3D matrix adhesions in normal stroma also taught in Franco-Barraza, see entire Franco-Barraza abstract.
Detjen teaches interferon gamma (IFNg) inhibits growth of human pancreatic carcinoma in vitro, as well as in vivo, see page 251, complete sentence at bottom of column 1. With the administration of IFNg T lymphocytes would be primed.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of all four references to utilize the 3D matrix adhesions in isolated desmoplasia stroma to address the expression of stromal α5β1 -integrin after administering IFNg to detect differences in the stroma after the initiation of primed T lymphocytes because Jiang teaches “the FAK inhibitor VS-4718…in tumor cells [was] effective in increasing CD8+ cytotoxic T cell infiltration into the PDAC tumors in vivo.:, see page 1, 2nd column, last paragraph.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by the successful teachings in the references to assess and measure cancer biomarkers in an in vivo-like environment at different time points to determine if the administered treatments were effective and/or could be improved upon, as well as observe the differences the 3D matrix adhesions between desmoplastic stroma and normal stroma. Furthermore, the data of Jiang “…suggest that FAK inhibition increases immune surveillance programs in PDAC tumors by overcoming the fibrotic and inflammatory microenvironment rendering tumors more responsive to immunotherapy.”, see page 1, 2nd column. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of all the references to understand the mechanistic functions of α5β1-integrin and FAK in this 3D matrix and utilize gleaned information and evidence from the mouse model to establish and implement a method of treating human pancreatic cancer with a therapeutic regimen including VS-4718, IFNg and PD-1 and/or PD-L1 antibodies.
Conclusion
9. All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
10. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can normally be reached on 8AM-8PM, Monday through Friday.
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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
12 February 2026
/Alana Harris Dent/Primary Examiner, Art Unit 1643