Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 28 – 47 were pending. Claim 1 has been amended. Claims 28 – 47 are currently pending and are the subject of this Office Action.
REJECTIONS MAINTAINED IN MODIFIED FORM
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 28 – 38 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 28 recites “based on the determining, selecting a therapeutically effective amount of a dose of an IL-6 inhibitor” but neither the claims nor the specification defines what selecting an effective dose is based on in the method for inhibiting cytomegalovirus (CMV) reactivation. Thus, it is not clear how a therapeutically effective amount of a dose of an IL-6 inhibitor is determined.
Claims 29 – 38 depend from claim 28, either directly or indirectly, and thus inherit the deficiencies of claim 28.
Response to Arguments
On page 5, last paragraph, of the reply of 05/04/2026, Applicant argues that “[t]he phrase "based on the determining" establishes a logical sequence-first, one determines the CMV-seropositive status, and then, based on that determination (i.e., because the patient is CMV-seropositive), one selects an appropriate dose of an IL-6 inhibitor. A person of ordinary skill in the art would understand this to mean that the selection of the IL-6 inhibitor dose is responsive to the determination of CMV-seropositive status. This type of conditional/sequential claim language is widely used in method claims and would be understood by those of ordinary skill in the art.”
However, as recited in claim 1, the phrase “based on the determining” seems to require specific conditions for “selecting a therapeutically effective amount of a dose of an IL-6 inhibitor”, and it is not clear what the conditions are. As outlined in MPEP 2171, claims must particularly point out and distinctly claim the invention. The boundaries of the claimed invention or its metes and bounds must be perfectly clear so the public knows exactly what infringes and what does not.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 39, 42, 43, and 47 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by KENNEDY (Kennedy, Glen A et al. Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial, The Lancet Oncology, Volume 15, Issue 13, 2014, Pages 1451-1459: PTO-892: Notice of References Cited of 12/04/2025).
Present independent claim 39 is directed to a method comprising determining that a human subject that will receive a bone marrow transplant or a stem cell transplant has a cytomegalovirus (CMV)-seropositive serological status; based on the determining, selecting a therapeutically effective amount of a dose of tocilizumab, wherein the therapeutically effective amount of the dose (i) blocks IL-6 function and (ii) prolongs the persistence of human subject-derived CMV-specific IgG, and administering the selected dose of the tocilizumab to the human subject only once, the administering commencing within 24 hours before the bone marrow transplant or stem cell transplant.
KENNEDY is directed to interleukin 6, which mediates graft-versus-host disease (GVHD) in experimental allogeneic stem-cell transplantation (allogeneic SCT) and represents an attractive therapeutic target. See Summary: Background, p. 1451. KENNEDY teaches that one intravenous dose of tocilizumab (8 mg/kg, capped at 800 mg, over 60 mins' infusion) was given the day before allogeneic SCT (see Summary: Methods, p. 1451 and Procedures, p. 1452), that the patients were tested for Cytomegalovirus status (see Table 1, p. 1453), and that “Cytomegalovirus reactivation occurred in only five (16%) of 31 seropositive recipients” (see p. 1455, right column). After the administration prior to the transplant, patients were both untreated and treated with tocilizumab at day 30 (see Procedures, second paragraph, p. 1452, right column), meaning that some patients were treated only once – prior to the transplant. Thus, KENNEDY teaches determining that a human subject that will receive a stem cell transplant has a cytomegalovirus (CMV)-seropositive serological status; based on the determining, selecting a therapeutically effective amount of a dose of tocilizumab and administering the selected dose of the tocilizumab to the human subject only once, the administering commencing within 24 hours before the stem cell transplant of present claim 39.
While KENNEDY does not expressly state that the disclosed method would prolong the persistence of human subject-derived CMV-specific IgG, the active steps taught by KENNEDY anticipate the method (of claim 39) that results in this observation and therefore the taught method by KENNEDY would inherently prolong the persistence of human subject-derived CMV-specific IgG. Importantly, KENNEDY teaches the connection between the administration of tocilizumab and the reduction of CMV reactivation.
Thus, KENNEDY anticipates present claim 39.
Regarding claim 42, KENNEDY teaches that the transplant is a stem cell transplant. See Procedures, first paragraph, p. 1452, right column.
Regarding claim 43, KENNEDY teaches that the patients have Myelodysplasia, Lympho-/Myeloproliferative disorders (see Table 1, p. 1453), which are immune system disorders.
Regarding claim 47, KENNEDY teaches that the administering is intravenous administering. See Summary: Methods, p. 1451.
Response to Arguments
On page 6, second and third paragraphs under “II. Claim Rejections under 35 U.S.C. § 102”, of the reply of 05/04/2026, Applicant argues that “[i]Independent claim 39 requires, inter alia, ‘based on the determining, selecting a therapeutically effective amount of a dose of tocilizumab, wherein the therapeutically effective amount of the dose (i) blocks IL-6 function and (ii) prolongs the persistence of human subject- derived CMV-specific IgG.’ This limitation requires a causal nexus between the CMV- seropositive determination and the dose selection-the dose must be selected because the patient is CMV-seropositive. Kennedy does not teach this causal link. In Kennedy, tocilizumab was administered to all patients regardless of and not based on a determination of CMV- seropositive status. Kennedy does not describe CMV status playing any role in the decision to administer tocilizumab or in selecting the dose. The claim requires that the dose selection be predicated on the CMV status determination, which is not taught. Moreover, the Office Action states that Kennedy teaches the connection between the administration of tocilizumab and the reduction of CMV reactivation. OA, page 4. This statement is incorrect. Kennedy had no control group from which such a connection could be drawn.”
Applicant’s argument is not persuasive because KENNEDY directly addresses the results of tocilizumab administration on CMV-reactivation: “Cytomegalovirus reactivation occurred in only five (16%) of 31 seropositive recipients.” See KENNEDY at p. 1455, right column, second to last sentence. Thus, in KENNEDY, the CMV serostatus of the patients prior to administration of tocilizumab were determined: there were 31 seropositive recipients. Of the 31 seropositive patients, only 5 (16%) had CMV reactivation after tocilizumab administration. Thus, KENNEDY anticipates the methods of present claims 39, 42, 43, and 47.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 28, 31 – 33 and 36 – 38 are rejected under 35 U.S.C. 103 as being unpatentable over REEVES (Reeves et al. Inhibition of inflammatory interleukin-6 activity via extracellular signal-regulated kinase-mitogen-activated protein kinase signaling antagonizes human cytomegalovirus reactivation from dendritic cells. J Virol. 2011; see PTO-892 of 02/01/2024) in view of ABBOUD (Abboud et al. Severe cytokine-release syndrome after T cell-replete peripheral blood haploidentical donor transplantation is associated with poor survival and anti-IL-6 therapy is safe and well tolerated Biol Blood Marrow Transplant, 22 (2016); see PTO-892 of 02/01/2024).
Present independent claim 28 is directed to a method for inhibiting cytomegalovirus (CMV) reactivation, the method comprising: determining that a human subject that will receive a bone marrow transplant or a stem cell transplant-has a CMV-seropositive serological status; based on the determining, selecting a therapeutically effective amount of a dose of an IL-6 inhibitor that (i) blocks IL-6 function and (ii) prolongs the persistence of human subject-derived CMV-specific IgG in the human subject; and administering the selected dose of the IL-6 inhibitor to the human subject, thereby inhibiting CMV reactivation in the human subject.
REEVES is directed to the major role for interleukin-6 (IL-6) through extracellular signal-regulated kinase–mitogen-activated protein kinase (ERK-MAPK) signaling upon DC differentiation to promote HCMV reactivation. REEVES discloses that the interception of IL-6 signaling with biological inhibitors significantly abrogated HCMV reactivation from experimental latency. See abstract. REEVES discloses that neutralizing IL-6 antibodies reduced HCMV reactivation and may be useful for therapeutic intervention of HCMV reactivation in transplant patients. See abstract and Conclusion.
REEVES teaches that:
1) “HCMV pathogenesis occurs following the reactivation of an existing HCMV latent infection” and that “the ability of HCMV to establish lifelong infection in humans and reactivate with devastating clinical consequences underscores the importance of understanding the triggers of HCMV reactivation” (see Introduction);
2) “[c]linically, HCMV reactivation occurs in highly inflammatory environments (i.e., transplantation)” (see abstract); and
3) “the interception of IL-6 signaling with biological inhibitors significantly abrogated HCMV reactivation from experimental latency” (see abstract).
REEVES teaches that HCMV seropositivity and elevated IL-6 levels are associated with increased risk for disease following bone marrow transplantation. See p. 12757-left column.
Thus, because REEVES teaches that HCMV reactivation occurs in patients who already have a latent HCMV infection which can reactivate with bone marrow transplantation, making it important to determine whether the patient has an infection prior to the transplant and because REEVES teaches that IL-6 inhibitors significantly abrogated HCMV reactivation, it would have been obvious to inhibit CMV reactivation by determining a CMV-seropositive serological status and selecting a therapeutically effective amount of a dose of an IL-6 inhibitor that blocks IL-6 function.
While REEVES’ experiments are performed on human cells from donors, REEVES’ method is not applied to human subjects and REEVES’ IL-6 inhibitor is not tocilizumab. However, ABBOUD teaches the administration of an IL-6 inhibitor tocilizumab to human subjects.
ABBOUD is directed to the treatment of cytokine-release syndrome (CRS) after T cell-replete peripheral blood haploidentical donor transplantation (haplo-HCT) with anti-IL-6 therapy, specifically with tocilizumab. See ABBOUD at the abstract. ABBOUD discloses that the most common source for haplo-HCT donor grafts is donor bone marrow. See Introduction, p. 1851, right column. ABBOUD teaches that the IL-6 inhibitor tocilizumab was administered after transplantation to CMV-seropositive and CMV-seronegative patients See p. 1853, Table 2.
Thus, ABBOUD teaches that CRS, like CMV reactivation, is marked by elevated IL-6 levels in transplant patients. Furthermore, ABBOUD teaches that this adverse condition may be successfully treated with an IL-6 inhibitor such as tocilizumab.
Regarding claim 28, because REEVES teaches that CMV reactivation often occurs in transplantation, occurs in seropositive cells, and is abrogated by an IL-6 inhibitor and ABBOUD teaches that transplant patients may suffer from IL-6 related CRS, which is successfully treated with the IL-6 inhibitor tocilizumab, it would have been obvious to inhibit CMV reactivation in a human subject who will receive a bone marrow transplant or a stem cell transplant and who has a CMV-seropositive serological status with a therapeutically effective amount of a dose of an IL-6 inhibitor.
While neither REEVES nor ABBOUD expressly state that the disclosed methods would result a prolonged persistence of human subject-derived CMV-specific IgG, the active steps (administrating an IL-6 inhibitor, particularly the claimed tocilizumab, to treat CMV) taught by REEVES render this observation obvious and therefore the method taught by REEVES in view of ABBOUD would inherently achieve a prolonged persistence of human subject-derived CMV-specific IgG.
At the effective filing date of the present claims, it would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of REEVES and ABBOUD. The artisan would have been motivated to use the methods of claims 28, 31 – 33 and 36 – 38 because REEVES teaches that “the modulation of IL-6 could have important implications for future therapeutic strategies” (see REEVES at Conclusion, p. 12757, left column, last sentence) and ABBOUD teaches that the IL-6 inhibitor “Tocilizumab was well tolerated with no adverse events attributable to therapy” when administered to stem cell transplant patients (haplo-HCT) (see ABBOUD at the first paragraph of DISCUSSION, p. 1856). Thus, the artisan would have a reasonable expectation of success that ABBOUD’s method of administering the IL-6 inhibitor tocilizumab to a transplant patient would also inhibit CMV reactivation because REEVES teaches that an IL-6 inhibitor inhibits CMV reactivation.
Regarding claim 31, ABBOUD discloses the IL-6 inhibitor is a monoclonal antibody is tocilizumab. See abstract.
Regarding claims 32 – 33, ABBOUD teaches he most common source for haplo-HCT donor grafts is donor bone marrow and also teaches that blood stem cells is a donor option. See Introduction, p. 1851, right column.
Regarding claims 36 – 37, REEVES discloses that venous blood samples were collected (see Materials and Methods: Ethics statement, p. 12751, left column, penultimate paragraph) and “[f]or detection of naturally latent HCMV gene expression, a nested PCR was performed with 5 μl of the primary PCR (30 cycles)” (see Materials and Methods: Nucleic acid isolation, RT, and PCR, p. 12751, right column, last paragraph).
Regarding claim 38, ABBOUD discloses that “[p]atients were treated with a single intravenous dose of tocilizumab (4 mg/kg of actual body weight). The median day of treatment was day +3 (range, 1 to 5)”. See Treatment with Tocilizumab, p. 1856, left column.
Response to Arguments
On page 6, last paragraph – page 9, second to last paragraph, of the reply of 05/04/2026, Applicant disagrees regarding the pending 103 rejections based on REEVES and ABBOUD, arguing that “the combination of Reeves and Abboud does not teach or suggest: determining that a human subject that will receive a bone marrow transplant or a stem cell transplant-has a CMV-seropositive serological status; and based on the determining, selecting a therapeutically effective amount of a dose of a an IL-6 inhibitor, and administering the selected dose of the IL-6 inhibitor to the human subject” (p. 7, second paragraph).
Applicant’s arguments are not persuasive because REEVES teaches that “the interception of IL-6 signaling with biological inhibitors significantly abrogated HCMV reactivation from experimental latency” and that “[c]linically, HCMV reactivation occurs in highly inflammatory environments (i.e., transplantation)” (see REEVES at the abstract), and ABBOUD teaches the administration of the IL-6 inhibitor tocilizumab to stem cell transplant patients who are CMV-seropositive (see abstract and Table 2, p. 1853).
At the effective filing date of the present claims, it would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of REEVES and ABBOUD. The artisan would have been motivated to use the methods of claims 28, 31 – 33 and 36 – 38 because REEVES teaches that “the modulation of IL-6 could have important implications for future therapeutic strategies” (see REEVES at Conclusion, p. 12757, left column, last sentence) and ABBOUD teaches that the IL-6 inhibitor “Tocilizumab was well tolerated with no adverse events attributable to therapy” when administered to stem cell transplant patients (haplo-HCT) (see ABBOUD at the first paragraph of DISCUSSION, p. 1856). Thus, the artisan would have a reasonable expectation of success that ABBOUD’s method of administering the IL-6 inhibitor tocilizumab to a transplant patient would also inhibit CMV reactivation because REEVES teaches that an IL-6 inhibitor inhibits CMV reactivation.
On p. 7, last two sentences – p. 8, first paragraph of the reply, Applicant argues that REEVES included other criteria that may be involved in CMV reactivation. However, the focus of REEVES is on the role of IL-6 on HCMV reactivation, which REEVES found to be significant. Although factors other than IL-6 may be involved in HCMV reactivation, REEVES clearly implicates IL-6 in HCMV reactivation mechanism. Thus, one having ordinary skill in the art would focus on inhibiting HCMV reactivation by inhibiting IL-6 from the disclosure of REEVES.
On p. 8, of the reply, Applicant states arguments form the Degli-Esposti Declaration of 07/19/2025 which has been addressed in the Office Action of 12/04/2025, arguing that “Abboud is cited for teaching the successful administration of an IL-6 inhibitor to human subjects to treat cytokine-release syndrome (CRS) after T cell-replete peripheral blood haploidentical donor transplantation (haplo-HCT). OA, pages 8-9. Abboud's successful treatment of CRS with an IL-6 inhibitor after haplo-HCT does nothing to overcome Reeve's statements regarding his own work and the conclusions that should be drawn from it. Abboud was studying CRS, not CMV reactivation” (p. 8, fifth paragraph).
Applicant’s argument is not persuasive because REEVES teaches that inhibiting IL-6 abrogates HCMV reactivation, and ABBOUD teaches that an IL-6 inhibitor can be safely administered to stem cell transplant patients who are CMV seropositive. Thus, REEVES in view of ABBOUD renders the method of inhibiting CMV reactivation in human subjects obvious.
On p. 8, bottom – 9, prior to part B., of the reply, Applicant argues that “(3) The Inherency Position Based on Reeves And Abboud is Incorrect” and states that “[f]or example, Jordan, cited by the Examiner, directly contradicts the inherency position by teaching the opposite-that tocilizumab reduces IgG levels, including "significant reductions in serum levels of IgG and IgA." Jordan, page 392. Further, as attested in the previously submitted July 19, 2025 Expert Declaration” and that “[b]ecause IL-6 inhibition can both prolong the persistence of and decrease IgG levels, there is no evidence that the specific combination of Reeves and Abboud would necessarily result in prolonged persistence”.
Applicant’s argument is not persuasive because the claimed tocilizumab of present claims 31 39 has the same structure as JORDAN’s (see 103 rejection below) tocilizumab, and thus would affect CMV-specific IgG levels in the human body in the same way (see discussion below). There are no limitations in claim 28 that distinguishes the claimed method from the method rendered obvious by REEVES and ABBOUD and thus prolong the persistence of human subject-derived CMV-specific IgG in a human subject any more than REEVE’s or ABBOUD’s IL-6 inhibitor would.
Claims 29, 39, 41 – 43 and 45 – 47 are rejected under 35 U.S.C. 103 as being unpatentable over REEVES in view of ABBOUD as applied to claims 28, 31 – 33 and 36 – 38 above, and further in view of KENNEDY.
The teachings of KENNEDY, REEVES and ABBOUD are discussed above and incorporated here. Although the method of claim 28, from which claim 29 depends, is rendered obvious by REEVES in view of ABBOUD, neither REEVES nor ABBOUD expressly teaches the limitations of present claim 29.
Regarding claims 29 and 39, because REEVES implicates IL-6 in CMV reactivation and KENNEDY teaches that one dose of the IL-6 inhibitor tocilizumab one day before the stem-cell transplant was successful in treating another IL-6-dependent disease, GVHD, in humans (see KENNEDY at Summary: Methods, p. 1451), it would have been obvious to administer an anti-IL-6 inhibitor or tocilizumab only once and within 24 hours before the bone marrow transplant or stem cell transplant, as taught by KENNEDY, in a method for inhibiting CMV reactivation, as taught by REEVES.
Furthermore, REEVES teaches the characterization of a specific cytokine (IL-6) that promotes the reactivation of naturally latent HCMV ex vivo and, more importantly, illustrates a potential mechanism to limit reactivation from these cells. See conclusions last paragraph. Thus, because IL-6 is directly implicated in CMV reactivation, which often happens in transplantation as discussed above, it would have been obvious to administer an IL-6 inhibitor (such as tocilizumab, as taught by ABBOUD) prior to transplantation in patients with latent CMV (CMV-seropositive).
Regarding claims 41 – 42, ABBOUD teaches he most common source for haplo-HCT donor grafts is donor bone marrow and also teaches that blood stem cells is a donor option. See Introduction, p. 1851, right column.
Regarding claim 43, KENNEDY teaches that the patients have Myelodysplasia, Lympho-/Myeloproliferative disorders (see Table 1, p. 1453), which are immune system disorders.
Regarding claim 45 – 46, REEVES discloses that venous blood samples were collected (see Materials and Methods: Ethics statement, p. 12751, left column, penultimate paragraph) and “[f]or detection of naturally latent HCMV gene expression, a nested PCR was performed with 5 μl of the primary PCR (30 cycles)” (see Materials and Methods: Nucleic acid isolation, RT, and PCR, p. 12751, right column, last paragraph).
Regarding claims 47, ABBOUD discloses that “[p]atients were treated with a single intravenous dose of tocilizumab (4 mg/kg of actual body weight). The median day of treatment was day +3 (range, 1 to 5)”. See Treatment with Tocilizumab, p. 1856, left column.
At the effective filing date of the present claims, it would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of REEVES, ABBOUD and KENNEDY. The artisan would have been motivated to use the methods of claims 29, 39, 41 – 43 and 45 – 47 because REEVES teaches that “the modulation of IL-6 could have important implications for future therapeutic strategies” (see REEVES at Conclusion, p. 12757, left column, last sentence); ABBOUD teaches that “Tocilizumab was well tolerated with no adverse events attributable to therapy” when administered to stem cell transplant patients (haplo-HCT) (see ABBOUD at the first paragraph of DISCUSSION, p. 1856); and KENNEDY teaches that Cytomegalovirus reactivation occurred in only five (16%) of 31 seropositive recipients after the administration of tocilizumab (See KENNEDY at p. 1455, right column, second to last sentence). Thus, the artisan would have a reasonable expectation of success of that ABBOUD’s or KENNEDY’s method of administering the IL-6 inhibitor tocilizumab to a transplant patient would also inhibit CMV reactivation because REEVES teaches that an IL-6 inhibitor inhibits CMV reactivation.
Response to Arguments
On page 9, part B, last paragraph, – page 10, first paragraph, of the reply of 05/04/2026, Applicant argues that “[t]he deficiencies of the base combination of Reeves and Abboud are described above and incorporated here. The addition of Kennedy does not remedy these deficiencies.” However, the application of REEVES, ABBOUD, and KENNEDY in the rejections of the present claims are discussed above and the rejections are maintained.
Claims 30 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over REEVES in view of ABBOUD and KENNEDY as applied to claims 28 – 29, 31 – 33, 36 – 39, 41 – 43 and 45 – 47, and further in view of JASKULA (Jaskula E, et al. CMV Serostatus of Donor-Recipient Pairs Influences the Risk of CMV Infection/Reactivation in HSCT Patients. Bone Marrow Res. 2012; see PTO-892 of 10/24/2024).
The teachings of KENNEDY, REEVES and ABBOUD are presented above and are incorporated herein. Although REEVES in view of ABBOUD teaches the method of claim 28, from which claim 30 depends, and KENNEDY teaches the method of claim 39, from which claim 40 depends, neither REEVES, ABBOUD nor KENNEDY expressly teaches the limitations of present claims 30 and 40.
JASKULA is directed to CMV donor/recipient serostatus that was analyzed in 200 patients allografted. See Abstract.
Regarding claims 30 and 40, JASKULA discloses that IgG and IgM ELISA test system was used for qualitative detection of CMV-specific antibodies in donors’ and recipients’ plasma and that the patients were routinely followed for clinical outcome in one-week intervals until 30 days posttransplant, then monthly until one-year post-transplant and as well as when clinical symptoms were suggestive of CMV, EBV, or HHV6 reactivation or any other serious post-transplant complications. Thus, because REEVES teaches a method of inhibiting CMV reactivation with an anti-IL-6 inhibitor and JASKULA teaches the monitoring of CMV-specific IgG 30 days in humans post-transplant with an ELISA assay, it would have been obvious to combine the methods of REEVES and JASKULA to arrive to the invention of claims 30 and 40.
At the effective filing date of the present claims, it would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of REEVES, ABBOUD, KENNEDY and JASKULA. The artisan would have been motivated to use the methods of claims 30 and 40 because REEVES teaches that “the modulation of IL-6 could have important implications for future therapeutic strategies” (see REEVES at Conclusion, p. 12757, left column, last sentence); ABBOUD teaches that “Tocilizumab was well tolerated with no adverse events attributable to therapy” when administered to stem cell transplant patients (haplo-HCT) (see ABBOUD at the first paragraph of DISCUSSION, p. 1856); KENNEDY teaches that Cytomegalovirus reactivation occurred in only five (16%) of 31 seropositive recipients after the administration of tocilizumab (See KENNEDY at p. 1455, right column, second to last sentence); and JASKULA teaches the monitoring of CMV-specific IgG. Thus, the artisan would have a reasonable expectation of success from the combined teachings of REEVES, ABBOUD, KENNEDY and JASKULA.
Response to Arguments
On page 10, part C, of the reply of 05/04/2026, Applicant states that ‘[t]he deficiencies of the base combination of Reeves and Abboud are described above and incorporated here. The addition of Kennedy and Jaksula does not remedy these deficiencies.”
The application of REEVES, ABBOUD, KENNEDY and JASKULA to the rejections of the present claims are discussed above and the rejections are maintained.
Claims 34 – 35 and 43 – 44 are rejected under 35 U.S.C. 103 as being unpatentable over REEVES in view of ABBOUD and KENNEDY as applied to claims 28 – 29, 31 – 33, 36 – 39, 41 – 43 and 45 – 47 and further in view of JORDAN.
The teachings of REEVES, ABBOUD, and KENNEDY are presented above and are incorporated herein. Although REEVES in view of ABBOUD teaches the method of claim 28, from which claims 34 – 35 depend, and KENNEDY teaches the method of claim 39, from which claims 43 – 44 depend, neither REEVES, ABBOUD nor KENNEDY expressly teaches the limitations of present claims 34 – 35 and 43 – 44.
JORDAN is a review article disclosing “new advances emerging from therapies aimed at treating autoimmunity and malignant disease of B cells and plasma cells, which are likely to improve the rates and success of incompatible transplantation in the future” (see p. 378, first paragraph).
Regarding claims 34 – 35 and 43 – 44, JORDAN discloses that “[a]dvances in understanding B-cell biology and the subsequent development of targeted therapeutic agents have had a major impact on reducing human suffering from inflammatory and autoimmune diseases” and that “these advancements will continue to improve the lives of sensitized solid organ transplant recipients” (see Conclusion and future perspective; last paragraph).
Considering that B cells produce IL-6 which are associated with autoimmune diseases and that the antibody tocilizumab has been approved by FDA to treat the autoimmune disease rheumatoid arthritis, as taught by JORDAN (see B cells as mediators of allo-sensitization & ABMR, p. 378, second column; Tocilizumab, p. 392, second column), it would have obvious to a person of ordinary skill in the art to modify the IL-6-targeting method of REEVES to apply to transplant recipients with immune or autoimmune disorders as described by JORDAN to arrive at the methods of present claims 34 and 35.
At the effective filing date of the present claims, it would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of REEVES, ABBOUD, KENNEDY and JORDAN. The artisan would have been motivated to use the methods of claims 34 – 35 and 43 – 44 because REEVES teaches that “the modulation of IL-6 could have important implications for future therapeutic strategies” (see REEVES at Conclusion, p. 12757, left column, last sentence); ABBOUD teaches that the IL-6 inhibitor “Tocilizumab was well tolerated with no adverse events attributable to therapy” when administered to stem cell transplant patients (haplo-HCT) (see ABBOUD at the first paragraph of DISCUSSION, p. 1856); KENNEDY teaches that Cytomegalovirus reactivation occurred in only five (16%) of 31 seropositive recipients after the administration of tocilizumab (See KENNEDY at p. 1455, right column, second to last sentence); and JORDAN teaches the IL-6 inhibitor Tocilizumab was recently approved by the FDA for treatment of several immune/autoimmune disorders (see JORDAN at Tocilizumab, p. 392, right column). Thus, the artisan would have a reasonable expectation of success from the combined teachings of REEVES, ABBOUD, KENNEDY and JORDAN.
Response to Arguments
On page 10, part D – p. 13, last paragraph of the reply of 05/09/2026, Applicant argues against the application of JORDAN in the rejections of the claims and that JORDAN teaches that “Jordan teaches that the use of tocilizumab in transplant recipients reduces transplant recipient immunity by reducing serum levels of IgG and IgA. Jordan, p. 392. Because Jordan teaches reducing a patient's pre-existing immunity (i.e., weakening the subject's immune system), Jordan provides no reasonable expectation that administering an IL- 6 inhibitor could reduce CMV reactivation following a transplant through utilizing a dose that protects immunity by prolonging the persistence of human subject-derived CMV-specific IgG. As stated by Dr. Degli-Esposti in her January 23, 2025 Expert Declaration, "the teachings of Jordan do not provide a reasonable expectation that an IL-6 inhibitor could be used to prolong the persistence of CMV-specific IgG as it teaches the opposite - that an IL-16 inhibitor reduces
antibody levels in a transplant recipient." Id. at paragraph 14” (bottom of p. 12 – top of p. 13 of the reply).
JORDAN is applied to show that tocilizumab can be administered to patients with an immune or autoimmune disorder as recited in present claim 34, 35, 43 or 44. JORDAN is applied in conjunction with REEVES, ABBOUD and KENNEDY. REEVES in view of ABBOUD teaches the method of inhibiting CMV reactivation of present claim 28, from which claims 34 and 35 each depends; KENNEDY teaches the method of claim 39, from which claims 43 and 44 each depends; and JORDAN teaches that tocilizumab may be administered to a subject, wherein the subject has immune disorder (of present claim 34 or 43) or wherein the subject has an autoimmune disorder (of present claim 35 or 44).
Although JORDAN teaches that Tocilizumab treatment can also result in a reduction of peripheral pre- and postswitch memory B cells in rheumatoid arthritis patients. These patients also showed significant reductions in IgG+ and IgA+ B cells and reduction in serum levels of IgG and IgA”, JORDAN does not teach that tocilizumab reduces CMV-specific IgG specifically, but seems to imply that general levels of IgG and IgA are affected.
Conclusion
Claims 28 – 47 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/ESTELLA M. GUSTILO/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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