DETAILED ACTION
1. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/17/2026 has been entered.
2. Claims 24, 66, 73, 79, 81-88 are pending and under examiantion.
3. Applicant’s IDS, filed 02/17/2026, is acknowledged.
4. 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.
5. Claims 24, 66, 73, 79 and 81-88 are rejected under 35 U.S.C. 103 as being unpatentable over Lundin et al. (Inflammatory Bowel Diseases 22:S30-S31, 2015, Abs P-067) or Floisand et al (Blood (Dec. 3, 2015) 126 (23): 3137, IDS), each in view of Ram et al (Leuk Lymphoma 54(8):1591-1601, 2013, IDS) and US 20190183930 and Avanzini et al. (Experimental Hematology 34 (2006) 1429–1434) and Koura et al (Biol Blood Marrow Transplant 19 (2013) 1638e1649).
Lundin et al Grade III-IV graft versus host disease (GvHD) after allogeneic bone marrow transplantation is associated with poor outcome and high mortality. Steroids are first line treatment, followed by several options for treatments with suboptimal effect and evidence. Furthermore, treatment modalities involve systemic immunosuppression, with risk of mortality due to infections. Vedolizumab (a humanized antibody against the α4β7 heterodimer comprising the claimed sequences), a monoclonal antibody targeting the homing of T cells to the intestinal endothelium through inhibition of the binding of integrin α4β7 to MadCAM, is effective in the treatment of inflammatory bowel disease. Lundin et al report the use of vedolizumab in 6 patients with steroid refractory, severe intestinal GvHD. They treated 6 patients in an open-label, investigator initiated case series. Patients 1 and 2 had been through therapy with several modalities without resolution of the severe GvHD. Patients 3 to 6 were given vedolizumab as second line therapy after steroid failure. Vedolizumab was given as described for IBD with 300 mg i.v. week 0, 2 and 6, followed by infusions every 8 weeks. Results: All patients (except number 4 that had multi-organ failure before receiving vedolizumab, and died soon thereafter) exhibited clinical response within 7-10 days after start of treatment with decrease in abdominal pain and watery diarrhea. Serial endoscopies were performed in remaining patients, and revealed rapid improvement in the upper GI-tract. In the colon, improvement was gradual, the caecum and distal ileum exhibited the slowest rate of repair. After 3 doses (i.e., Day 56) of vedolizumab, most patients could taper systemic corticosteroid therapy. All patients, except patient 4, were on oral medication including immunosuppressants (oral cyclosporin-A or MMF). Patient 1 is in continued clinical remission of GvHD. Patient 2 experienced a molecular relapse of acute promyelocytic leukemia (APL) (i.e., suffering from cancer) and his GvHD relapsed after cessation of immunosuppression. Patient 3 developed skin GvHD after cessation of immunosuppression and died of an opportunistic infection following treatment of high dose steroids. Patient 4 had multi-organ failure prior to start of treatment with vedolizumab and died. Patients 5 and 6 have no symptoms of serious GvHD after 2 and 3 doses of vedolizumab. Four out of 6 patients could be discharged from hospital. Immunophenotyping of peripheral blood revealed initial high levels of CD25+ Treg cells in 4 out of 6 evaluable patients and the values showed a decline into normal range after start of therapy and with signs of clinical effect. Conclusions: This case series suggests that targeting integrin α4β7 is feasible, safe and gives clinical responses in steroid refractory intestinal GvHD. The mechanism of action is not known, but may be due to the inhibition of allo-reactive T-cells homing to the intestinal mucosa. The mechanism behind the Treg patterns is unclear. One might speculate that the initially high levels of Tregs are part of the physiologic reaction to the alloreactive inflammation in the intestinal mucosa (abstract).
Floisand et al teach that targeting integrin α4β7-expressing T-cells in steroid refractory intestinal GvHD using Vedolezumab (comprising the claimed SEQ ID NOs) in six patients with intestinal Severe steroid refractory (SR) GvHD (after allo-HSCT). Vedo was delivered as prescribed in IBD; 300 mg iv without premedication week 0, 2 and 6, followed by (intravenous) infusions every 8 weeks on clinical indication (abstract). All patients exhibited clinical responses within 7 - 10 days after start of treatment with decrease in abdominal pain and watery diarrhea. Serial endoscopies were performed in patients 1,2,3,5 and 6. These revealed gradual macroscopic and histologic improvement; the upper GI-tract showing a more rapid improvement than the colon. Figure 1 shows colon histology before (a, b, c) and after 3 doses (56 Days) of Vedo (d, e, f) in patient 1, 2 and 3. Patient 1 is in continued clinical remission of GvHD 8 months (day +240) after start of therapy. Patient 2 was asymptomatic for 5 months (day +150), then a molecular relapse of acute promyelocytic leukemia (cancer) was diagnosed and intestinal GvHD recurred when all immunosuppression was stopped. In patient 3, the intestinal GvHD resolved after three doses of Vedo, but he developed skin GvHD after cessation of IS and died of an opportunistic infection following treatment with high dose methylprednisolone. Patient 4 had MOF prior to start of treatment with Vedo and died in MOF. Patient 5 and 6 have no clinical signs of intestinal GvHD after 2 and 3 doses of Vedo. Five out of six patients could be discharged from hospital after treatment with Vedo. All patients were diagnosed with either AML (leukemia) or NHL (lymphoma) (see table 1). Floisand et al teaches that immunophenotyping of peripheral blood revealed high levels of CD25+ Treg cells in 4 out of 5 evaluable patients prior to treatment and the numbers decreased to normal levels after start of therapy and with signs of clinical effect. Patient 2 stopped IS after a molecular relapse of APL and had a recurrence of GvHD. This recurrence coincided with an increase in Treg percentage. This case series provides the first proof of concept that targeting integrin α4β7 T-cells is feasible, safe and may provide clinical improvement in intestinal SR GvHD. The mechanism of action is not known, but may be due to the inhibition of the homing of α4β7 expressing allo-reactive T-cells to recipient MadCAM expressing intestinal endothelial cells (see the entire document).
The reference teachings differ from the claimed method only in the recitation of administration of tacrolimus before allo-HSCT and wherein tacrolimus administration is continued for 100 days after allo-HSCT and wherein methotrexate is administered to the human patient after the allo-HSCT and the administration vedolizumab day -1 in claims 24 and 66.
Ram et al on Table 1 shows methotrexate as a common GVHD prophylaxis medication with associated regimens given on day +1, +3, +6 or +11 (i.e., after allo-HSCT) (see page 4, under Cycloporine). Ram et al further teaches that tacrolimus is common GVHD prophylaxis medication with associated regimens starting on day -3 to day -1 (Table 1) (before allo-HSCT).
The `930 publication teaches a GvHD regimen is as follows. Tacrolimus will be given as 0.03 mg/kg/day IV infusion beginning on day +5 and converted to oral tacrolimus when PO intake is tolerated. Tacrolimus will be continued until day +100 and then may be tapered to none by day +180 relative to day 0 if there is no evidence of active GvHD [0059], [0084], [0086] and Table on page 9, wherein the subject has a condition that is treatable by HSCT wherein the condition is selected from: acute lymphoblastic leukemia (ALL); relapsed ALL; Hodgkin lymphoma (HL); Non-Hodgkin lymphoma (NHL); relapsed HL or NHL; acute myeloid leukemia (AML); relapsed AML; chronic myeloid leukemia (CML) and myelodysplastic syndrome (MDS) (see published claim 37).
Avanzini et al teach that their data provide information potentially useful to identify in a timely manner a population of patients at high risk of experiencing intestinal a-GVHD (i.e., a-GVHD beginning before day +100 after HCT) and to design strategies based on the use of compounds, such as humanized antibodies against the α4β7 heterodimer, which could hamper alloreactive T-cell homing to intestinal tissue. This, in turn, could result in significant improvement in the prevention and/or treatment of intestinal GVHD and overall morbidity and mortality from GVHD (page 1433, last ¶). Avanzini teaches that measuring the absolute number of CD8(+) T cells and percentage of CD8(+)CD45RA(+)beta7(+) T cells at time of hematologic reconstitution may help identify patients at risk of developing intestinal a-GVHD who could benefit from strategies aimed at hampering alloreactive T-cell homing to intestinal mucosa (abstract).
Koura et al performed a first-in-disease trial of in vivo CD28:CD80/86 costimulation blockade with abatacept for acute graft-versus-host disease (aGVHD) prevention during unrelated-donor hematopoietic cell transplantation (HCT). All patients received cyclosporine/methotrexate plus 4 doses of abatacept (10 mg/kg/dose) on days -1, +5, +14, +28 post-HCT. Compared with a cohort of patients not receiving abatacept (the StdRx cohort), patients enrolled in the study (the ABA cohort) demonstrated significant inhibition of early CD4+ T cell proliferation and activation, affecting predominantly the effector memory (Tem) subpopulation, with 7- and 10-fold fewer proliferating and activated CD4+ Tem cells, respectively, at day+28 in the ABA cohort compared with the StdRx cohort (abstract).
Regarding the recitation prevention of Grade III or IV aGvHD is “achieved 100 days following the allo-HSCT as compared to treatment with tacrolimus and methotrexate alone”, flow logically from the resultant method of treatment based on the combined reference teachings.
Claims 85-86 are included because the Lundin reference teaches that the patient 1 is in continued clinical remission of GvHD.
Claims 87-88 are included because the “further doses of the antibody, each administered about four weeks after the immediate prior dose”, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276, 205 USPQ 215,219 (CCPA 1980).
Those of skill in the art before the effective filing date of the instant application would start administering the vedolizumab one day prior to undergoing allo-HSCT transplant in the methods taught by Floisand et al and Lundin et al to inhibit allo-reactive T-cells homing to the intestinal mucosa in a method of preventing/prophylaxis and reducing GI aGvHD as taught by Koura, Lundin and Floisand references and/or to prevent trafficking of donor alloreactive T cells in the host prior to allo-HSCT transplant in patients undergoing HSCT as taught by Chen and Waldman.
Given that acute promyelocytic leukemia was diagnosed and intestinal GvHD recurred when all immunosuppression was stopped taught by Floisand et al, those of skill in the art would have had a reason to provide the appropriate immunosuppressive treatment by administer tacrolimus before allo-HSCT and continued for 100 days after allo-HSCT as taught by the `930 publication and Ram et al reference and administer methotrexate after allo-HSCT as taught by Ram et al reference to prevent the development of acute promyelocytic leukemia and intestinal GvHD recurrence as taught by Floisand and the `930 application.
The Vedo treatment protocol taught by Lundin and Floisand differ from treatment protocol recited in Claims 24 and 66 only in terms of duration of treatment, however, it would be conventional and within the skill of the art to identify and determine the optimum duration of treatment protocols to inhibition of allo-reactive T-cells homing to the intestinal mucosa in the treatment of GI GvHD. It would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal administration timing of components because optimal administration duration is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Accordingly, the specific vedolizuamb regimen claimed in claims 24 and 66, administering the vedo, waiting at least 12 hours, administering allo-HSC, wait 13 days then administer 2nd dose of vedo and wait 4/6 weeks then administer a 3rd dose of vedo is well within the purview of one of ordinary skill in the art prior to the effective filing date of the claimed invention and lends no patentable import to the claimed invention. Since the method is directed to GvHD prophylaxis, it would be obvious to inhibit prevent intestinal homing of alloreactive T cells in patients undergoing HSCT.
Further, the functions recited in the wherein clause “the allo-HSCT results in engraftment of the HSCs” flow naturally from the teachings of the prior art. (citing Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985 (“The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.”), and Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999) (“[T]he discovery of... a scientific explanation for the prior art's functioning, does not render the old composition patentably new to the discoverer.”)). The claimed function limitation would naturally and necessarily flow from inhibition of α4β7 with vedolizumab in vivo.
The Board in Genzyme Therapeutic Prods. v. Biomarin Pharms., No. 2015-1720 stated that "all that remained to be achieved over the prior art was the determination that a specific dose within a previously suggested dose range, and its corresponding dosing schedule, would have been safe and effective for the treatment of human patients."
"[I]t is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456 (CCPA 1955); see also In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003). "Only if the 'results of optimizing a variable' are 'unexpectedly good' can a patent be obtained for the claimed critical range." In re Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997) (quoting In re Antonie, 559 F.2d 618, 620 (CCPA 1977)). "[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276 (CCPA 1980).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat the allo-HSCT recipient with myeloablative conditioning regimens prior to the administration of vedolizumab in the treatment of APL, AML and NHL having GI GVHD because treating patients with myeloablative conditioning is traditionally done and to eliminate undesirable host-derived hematopoietic elements before BMT.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicant’s arguments, filed 02/17/2026, have been fully considered, but have not been found convincing.
Applicant points to Example 1 of the specification and Chen et al. (2019) Blood Advances 3(23): 4136-4146 ("Chen 2019") and Chen et al (Nat Med. 2024) (Chen 2024) for support for the claimed invention. Applicant asserts that the one of ordinary skill would not have had an expectation of success based on the teachings of the cited art tht administering the claimed antibody before allo-HSCT to a patient having acute lymphoblastic leukemia, wherein the patient is also administered tacrolimus and methotrexate, could reduce the cumulative incidence and severity of Grade III or IV acute GvHD 100 days following the allo-HSCT as compared to treatment with tacrolimus and methotrexate alone, as claimed, evidenced by Chen 2029 and Chen 2024.
This is not found persuasive because the prior art provides a reasonable expectation of success that the co-administration of anti-α4β7 antibody and standard calcineurin inhibitor, such as tacrolimus and methotrexate results in inhibiting allo-reactive T-cells homing to the intestinal mucosa in a method of preventing/prophylaxis and reducing GI aGvHD after hematopoietic stem cell transplantation (HCT) for leukemia. see O’Farrell, 853 F.3d 894, 903-04 (Fed. Cir. 1988) (“Obviousness does not require absolute predictability of success ... all that is required is a reasonable expectation of success.”). Our reviewing court has held that when the prior art does not expressly disclose a claim limitation, inherency may supply the missing element. See Persion Pharm. LLC v. Alvogen Malta Operations Ltd., Case No. 18-2361 (Fed. Cir. Dec. 27, 2019) and Hospira,Inc. v. Fresenius Kabi USA, LLC., Case No. 19-1329, 19-1367 (Fed. Cir. Jan. 9, 2020). “Inherency is established in the context of obviousness when ‘the limitation at issue necessarily must be present, or the natural result of the combination of elements explicitly disclosed by the prior art.’” Hospira, slip op. at 10 (Fed. Cir. Jan. 9, 2020) (citing Par Pharm. v. TWIPharm., Inc., 773 F.3d 1186, 1195—96 (Fed. Cir. 2014)). Here, the functions recited in the wherein clause flow naturally from the teachings of the prior art. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985 (“The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.”), and Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999) (“[T]he discovery of... a scientific explanation for the prior art's functioning, does not render the old composition patentably new to the discoverer.”)).
Here, the recited functional outcome would naturally and necessarily flow from inhibition of α4ß7 by co-administration of anti-α4β7 antibody and standard calcineurin inhibitor, such as tacrolimus and methotrexate results in inhibiting allo-reactive T-cells homing to the intestinal mucosa in a method of preventing/prophylaxis and reducing GI aGvHD after hematopoietic stem cell transplantation (HCT) for leukemia. Accordingly, the prior art teaches the same method, the product used in the reference method are the same as the claimed method. Therefore, the claimed functional outcome would naturally and necessarily flow from inhibition of α4ß7 via co-administration of anti-α4β7 antibody and standard calcineurin inhibitor, such as tacrolimus and methotrexate results in inhibiting allo-reactive T-cells homing to the intestinal mucosa in a method of preventing/prophylaxis and reducing GI aGvHD after hematopoietic stem cell transplantation (HCT) for leukemia.
Applicant submits that Lundin and Floisand, cited as primary references by the Office, describe treatment of GvHD in six patients with steroid refractory GvHD after All-HSCT with vedolizumab. As a first matte, Lundin and Floisand do not describe a patient having acute lymphoblastic leukemia, as required by the claims, and there is no teaching or suggestion in Lundin and Floisand that vedolizumab could work in a patient with a different cancer from that described therein. Moreover, Lundin and Floisand refer to steroid refractory GvHD patients and were given vedolizumab after steroid failure for treatment of GvHD. In particular, Lundin reports that “patient 4 had multi-organ failure prior to start of treatment with vedolizumab and died” (see Results). Floisand similarly repots that “patient 4 already had MOF with gastrointestinal GvHD before receiving Vedo, and died of MOF”. In contrast to Lundin and Floisand, the claimed invention specifics reducing the incidence and severity of aGvHD by administering a humanized antibody having binding specificity for human α4β7 integrin before allo-HSCT for acute lymphoblastic leukemia such that a patient does not develop as severe aGvHD as the patients described in Lundin and Floisand, and can therefore be treated for acute lymphoblastic leukemia.
This is not found persuasive because the claims do not recite that the claimed patient population are limited to steroid refractory GvHD having multi-organ failure (MOF). Importantly, all patients, except patient 4, were on oral medication including immunosuppressants (oral cyclosporin-A or MMF). While the claims require both vedolizumab and standard calcineurin inhibitor, patient 4 has MOF and did not receive immunosuppressants. Further, all patients (except number 4) exhibited clinical response within 7-10 days after start of treatment with decrease in abdominal pain and watery diarrhea. Patient 2 experienced a molecular relapse of acute promyelocytic leukemia (APL) (i.e., suffering from cancer) and his GvHD relapsed after cessation of immunosuppression. Four out of 6 patients could be discharged from hospital.
Similar to Example 1 of the specification, Lundin concluded that this case series suggests that targeting integrin α4β7 is feasible, safe and gives clinical responses in steroid refractory intestinal GvHD. The mechanism of action is not known, but may be due to the inhibition of allo-reactive T-cells homing to the intestinal mucosa. (abstract). Floisand et al teach that all patients exhibited clinical responses with 7-10 days after start of treatment with decreased in abdominal pain and watery diarrhea. Floisand teaches that five out of six patients could be discharged from hospital after treatment with Vedo. All patients were diagnosed with either AML (leukemia) or NHL (lymphoma) (see Table 1). Floisand concluded that this case series provides the first proof of concept that targeting integrin α4β7 T-cells is feasible, safe and may provide clinical improvement in intestinal SR GvHD. The mechanism of action is not known, but may be due to the inhibition of the homing of α4β7 expressing allo-reactive T-cells to recipient MadCAM expressing intestinal endothelial cells (see the entire document).
Applicant points to Hamadani et al. Biol Blood Marrow Transplant 2008 Jul;14(7):783-9 ("Hamadani") describes the results of "a prospective trial of infliximab for the prophylaxis of aGvHD" (see Abstract, sentence 2) in which "[r]esults were compared with a matched historic control group (see Abstract, sentence 7), and concluded that "[i]nfliximab use did not produce a significant improvement in the cumulative incidence of aGVHD" (see page 788, right col, penultimate sentence) despite "[a] number of retrospective studies [having] shown activity of [infliximab] in the treatment of steroid refractory aGVHD" (see page 783, right col, first complete sentence and sentence bridging pages 783-784). Hamadani describes a trial that included ALL patients (see Table 1, page 785) and states that, in contrast to GVHD treatment, "[t]he addition of infliximab to standard GVHD prophylaxis did not lower the risk of GVHD and was associated with an increased risk of bacterial and invasive fungal infections" (see Abstract, last sentence; emphasis added). Hamadani concludes that "[i]nfliximab is unlikely to make a major impact in controlling and preventing aGVHD following myeloablative conditioning at least in patients with high-risk hematologic malignancies" (see page 788, right col., last 2 sentences). Given the study described in Hamadani, which provided infliximab before (not treatment after) allo-HSCT and found that infliximab did not lower the risk of aGvHD, one of ordinary skill would not have had an expectation of success at the time of filing that a therapeutic that can treat aGvHD, as described in Lundin and/or Floisand, would also be able to reduce the cumulative incidence and severity of grade III or IV aGvHD, much less in patient undergoing allo-HSCT for treatment of ALL, as specified by the claims.
Applicant submits that although the Office asserts that the teachings of Hamadani "did not discourage Applicant from using vedolizumab to reduce the cumulative incidence and severity of grade III or IV acute GvHD in a patient having acute lymphoblastic leukemia, as claimed" (see Office Action, page 3, last para.), per MPEP § 2141.03, Subsection III, the "examiner must ascertain what would have been obvious as of the relevant time to one of ordinary skill in the art, and not to the inventor, a judge, a layman, those skilled in remote arts, or to geniuses in the art at hand. Environmental Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 218 USPQ 865 (Fed. Cir. 1983), cert. denied, 464 U.S. 1043 (1984)" (emphasis added). Applicant reiterates that in view of Hamadani, the teachings of Lundin and Floisand would not be suggestive to one of ordinary skill in the art that administering a humanized antibody having binding specificity for human a437 integrin could achieve a reduction in cumulative incidence and severity of aGvHD following allo-HSCT at 100 days as compared to treatment with tacrolimus and methotrexate alone, as claimed.
This is not found persuasive because Hamadani et al (Biol Blood Marrow Transplant 2008 Jul;14(7):783-9) was not use in the rejection. Further, it was known prior to Applicant filing date, Hamadani et al that "[i]nfliximab use did not produce a significant improvement in the cumulative incidence of aGVHD, may have delayed platelet engraftment, and was associated with frequent infectious complications. Infliximab is unlikely to make a major impact in controlling and preventing aGVHD following myeloablative conditioning at least in patients with high-risk hematologic malignancies", yet such teachings did not discourage Lundin, Floisand and Applicant from using vedolizumab to reduce the cumulative incidence and severity of grade III or IV acute GvHD in a patient having acute lymphoblastic leukemia, as claimed. There is no discouragement nor skepticism in the prior art for administering vedolizumab prophylaxis the day before allo-HSCT giving the teachings of Lundin and Floisand that targeting integrin αvβ7 with vedolizumab is feasible, safe and gives clinical responses in SR intestinal GvHD. There are no teachings in the prior art that vedolizumab causes unsatisfactory outcomes, complications and/or bacterial and invasive fungal infections. Given that acute promyelocytic leukemia was diagnosed and intestinal GvHD recurred when all immunosuppression was stopped taught by Floisand et al, those of skill in the art would have had a reason to provide the appropriate immunosuppressive treatment by administer tacrolimus before allo-HSCT and continued for 100 days after allo-HSCT as taught by the `930 publication and Ram et al reference and administer methotrexate after allo-HSCT as taught by Ram et al reference to prevent the development of acute promyelocytic leukemia and intestinal GvHD recurrence as taught by Lundin, Floisand and the `930 application.
Applicant submits that the combined teachings of Ram, the '930 publication, Avanzini, and Koura do not remedy the deficient teachings of Lundin and Floisand. Ram is cited for describing "methotrexate as a common GVHD prophylaxis medication with associated regimens given on day+ 1, +3, +6 or+ 11 (i.e., after allo-HSCT)" and that tacrolimus is common GvHD prophylaxis medication with associated regimens starting on day -3 to day -1" (see page 4, third full para. of the Office Action). However, in contrast to Ram, the claimed invention improves upon standard GvHD prophylaxis to achieve a reduction in cumulative incidence and severity of Grade III or IV aGvHD as compared to tacrolimus and methotrexate alone. Ram does not teach or suggest that administration of the claimed antibody before allo-HSCT can improve upon standard GvHD prophylaxis. Moreover, Applicant's specification states at page 3, lines 10-12 that "[f]or the prevention of GvHD... it is believed that the present invention blocks the initial trafficking of T cells to secondary lymphoid organs, e.g., PP or MLN, by interfering with the 37/MADCAM-1 pathway." Ram describes agents that target subsets of T cells for prophylaxis of GvHD at page 1597, right column, but does not teach or suggest agents that block T cell trafficking by blocking a437 integrin as possible agents for this purpose. Indeed, Ram states that "[s]o far, attempts to target the TTH and TH2cells and the corresponding cytokines have failed to result in conclusive and reproducible prevention of GVHD" (see page 1597, right col., last full para.; emphasis added). Thus, Ram teaches away from using agents to target T cells, e.g., by employing the mechanism of blocking a437 integrin and preventing T cell trafficking, to reduce the cumulative incidence and severity of acute GvHD.
However, it is the Examiner’s position that the recited functional outcome would naturally and necessarily flow from inhibition of α4ß7 by co-administration of anti-α4β7 antibody and standard calcineurin inhibitor, such as tacrolimus and methotrexate results in inhibiting allo-reactive T-cells homing to the intestinal mucosa in a method of preventing/prophylaxis and reducing GI aGvHD after hematopoietic stem cell transplantation (HCT) for leukemia. Accordingly, the prior art teaches the same method, the product used in the reference method are the same as the claimed method. Therefore, the claimed functional outcome would naturally and necessarily flow from inhibition of α4ß7 via co-administration of anti-α4β7 antibody and standard calcineurin inhibitor, such as tacrolimus and methotrexate results in inhibiting allo-reactive T-cells homing to the intestinal mucosa in a method of preventing/prophylaxis and reducing GI aGvHD after hematopoietic stem cell transplantation (HCT) for leukemia.
The '930 publication describes an immunosuppression regimen using tacrolimus for GvHD prophylaxis (see e.g., para. [0059]). However, as in Ram, nowhere does the '930 publication teach or suggest administering any agent to target T-cells to reduce the cumulative incidence and severity of aGvHD in combination with tacrolimus, let alone administration of the claimed antibody before allo-HSCT.
This is not found persuasive because the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference and not is it that the claimed invention must be expressly suggested in any one or all of the references; but rather the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). See MPEP 2145. In the instant case, the combined reference teachings arrived to the claimed invention.
Avanzini describes "measuring the absolute number of CD8+ T cells and percentage of CD8+CD45RA+p7+ T cells at time of hematologic reconstitution may help identify patients at risk of developing intestinal a-GVHD who could benefit from strategies aimed at hampering alloreactive T-cell homing to intestinal mucosa" (see 1429, "Conclusion"). Although, Avanzini states the data provide information potentially useful for designing "strategies based on the use of compounds, such as humanized antibodies against the a437 heterodimer, which could hamper alloreactive T-cell homing to intestinal tissue" (see page 1433, left col.), Avanzini, alone or in combination with the other cited art, does not teach or suggest administering a humanized antibody having binding specificity for human α4β7 integrin with tacrolimus before allo-HSCT and methotrexate after allo- HSCT to reduce the incidence and severity of Grade III or IV aGvHD, as specified by the claims.
Koura describes the prevention of aGvHD by administration of abatacept before allo-HSCT, however, Koura is silent with respect to an anti-α4β7 antibody. Abatacept is a recombinant fusion protein that interferes with the immune activity of T cells by preventing antigen-presenting cells from delivering CD28 co-stimulatory signals. There is no teaching or suggestion that abatacept's mechanism of action applies to an antibody with binding specificity for the α4β7 complex. Therefore, not only is Koura silent with respect to an anti-α4β7 antibody, but Koura is also silent with respect to mechanisms of preventing or reducing the cumulative incidence and severity of acute GvHD other than through costimulation blockade. One of ordinary skill would not have been motivated from the teachings of Koura to substitute abatacept with an antibody with a different mechanism before allo-HSCT, much less have an expectation of success that administering the claimed anti-α4β7 antibody with tacrolimus before allo-HSCT and methotrexate after allo-HSCT could achieve a reduction the incidence and severity of Grade III or IV aGvHD at 100 days after allo-HSCT, as claimed, and as evidenced by Chen 2019 and Chen 2024.
In sum, Lundin and Floisand describe treatment of aGvHD in steroid-refractory patients using vedolizumab, but do not teach or suggest reducing the cumulative incidence and severity of aGvHD by administering a humanized antibody having binding specificity for human a437 integrin before allo-HSCT for acute lymphoblastic leukemia such that a patient does not develop as severe aGvHD as the patients described in Lundin and Floisand. Ram and the '930 publication merely describe standard GvHD prophylaxis (e.g., tacrolimus and methotrexate) that Applicant's invention improves upon. Avanzini provides biomarker data that Avanzini states might be used to develop "strategies based on the use of compounds, such as humanized antibodies against the a437 heterodimer, which could hamper alloreactive T-cell homing to intestinal tissue" (see page 1433, left col.), but Avanzini does not teach or suggest administration of the claimed antibody before allo- HSCT could achieve a reduction in the cumulative incidence and severity of Grade III or IV acute GvHD 100 days following the allo-HSCT as compared to treatment with tacrolimus and methotrexate alone, as claimed. Koura describes the prevention of aGvHD through administration of abatacept before allo-HSCT but does not teach or suggest mechanisms of preventing or reducing the cumulative incidence and severity of acute GvHD other than through costimulation blockade. Thus, one of ordinary skill would could not have predicted based on the combined teachings of the cited art that administering a humanized antibody having binding specificity for human a437 integrin before allo-HSCT to a patient having acute lymphoblastic leukemia, wherein the patient is also administered tacrolimus and methotrexate, could reduce the cumulative incidence and severity of Grade III or IV acute GvHD 100 days following the allo-HSCT as compared to treatment with tacrolimus and methotrexate alone, as claimed, and as evidenced by Chen 2019 and Chen 2024.
This is not found persuasive because the combined reference teachings arrived to the claimed method recited in the claim. It is prima facie obvious to combine two compositions each of which is taught by prior art to be useful for same purpose in order to form third composition that is to be used for very same purpose; idea of combining them flows logically from their having been individually taught in prior art. In re Kerkhoven, 205 USPQ 1069, CCPA 1980. See MPEP 2144.06. Further, “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc. 550 U.S. 398, 416 (2007). The motivation to combine can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combine for their common known purpose. Section MPEP 2144.07. Importantly, Avanzini provides information potentially useful to identify in a timely manner a population of patients at high risk of experiencing intestinal a-GvHD and to design strategies abased on the use of compounds, such as humanized antibodies against the α4β7 heterodimer, which could hamper alloreactive T-cell homing to intestinal tissue. This in turn, could result in significant improvement in the prevention and/or treatment of intestinal GvHD and overall morbidity and mortality from GvHD (page 1433, last ¶).
It remains the Examiner’s position that those of skill in the art before the effective filing date of the instant application would start administering the vedolizumab one day prior to undergoing allo-HSCT transplant in the methods taught by Floisand et al and Lundin et al to inhibit allo-reactive T-cells homing to the intestinal mucosa in a method of preventing/prophylaxis and reducing GI aGvHD as taught by Koura, Lundin and Floisand references and/or to prevent trafficking of donor alloreactive T cells in the host prior to allo-HSCT transplant in patients undergoing HSCT as taught by Chen and Waldman.
Given that acute promyelocytic leukemia was diagnosed and intestinal GvHD recurred when all immunosuppression was stopped taught by Floisand et al, those of skill in the art would have had a reason to provide the appropriate immunosuppressive treatment by administer tacrolimus before allo-HSCT and continued for 100 days after allo-HSCT as taught by the `930 publication and Ram et al reference and administer methotrexate after allo-HSCT as taught by Ram et al reference to prevent the development of acute promyelocytic leukemia and intestinal GvHD recurrence as taught by Floisand and the `930 application.
6. No claim is allowed.
7. The art made of record and not relied upon is considered pertinent to applicant's disclosure:
Ganetsky et al. Higher tacrolimus concentrations early after transplant reduce the risk of acute graft-versus-host disease in reduced-intensity allogeneic stem cell transplantation. Bone Marrow Transplant. 2015 Dec 21;51(4):568–572.
All patients received standard GVHD prophylaxis with oral TAC (0.06 mg/kg/day) in two divided doses starting 3 days before HSCT and intravenous methotrexate (MTX) at a dose of 15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6, and 11. Antithymocyte globulin was not used in any of the patients. The dose of TAC was adjusted to a target trough level of 5 – 15 ng/mL and was continued through 100 days post-HSCT and then tapered. The standard at our institution is to obtain the first TAC trough concentrations 1 day prior to HSCT and then at least twice weekly and at least 72 hours after any dosage change to allow drug levels to achieve steady state (page 3, top ¶).
8. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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April 7, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644
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