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Claims 1 – 11, 13, and 16 – 27 were pending, with non-elected claims 3 – 4,7 – 9, and 16 – 20 withdrawn from consideration. Claims 1 – 11, 13, and 16 – 27 have been canceled, and claims 28 – 47 have been newly added. Claims 28 – 47 are currently pending and are the subject of this Office Action.
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 “a human subject” in line 1 but recites “a human subject” in line 3. Thus, it is not clear if “a human subject” in line 3 refers to the human subject in line 1 or another human subject separate from that in line 1.
Furthermore, 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 “based on the determining” means. 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.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed 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 submitted with this Office Action).
Present 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.
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.
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.
Previous rejection, withdrawn: claims 1 – 2, 5 – 6, 10 – 11, and 25 – 27 were 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).
In view of the cancelation of claims 1 – 2, 5 – 6, 10 – 11, and 25 – 27 in the reply of 08/20/2025, this rejection is withdrawn.
Previous rejection, withdrawn: claim 13 was rejected under 35 U.S.C. 103 as being unpatentable over REEVES in view of ABBOUD as applied to claims 1 – 2, 5 – 6, 10 – 11, and 25 – 27 and further in view of JORDAN (Jordan et al. Achieving Incompatible Transplantation through Desensitization: Current Perspectives and Future Directions. Immunotherapy 7.4 (2015); see PTO-892 of 02/01/2024).
In view of the cancelation of claim 13 in the reply of 08/20/2025, this rejection is withdrawn.
Previous rejection, withdrawn: claim 21 was rejected under 35 U.S.C. 103 as being unpatentable over REEVES in view of ABBOUD as applied to claims 1 – 2, 5 – 6, 10 – 11, and 25 – 27 and further in view of VO (Vo, A. et al. CLAZAKIZUMAB® (ANTI-IL-6) FOR DESENSITIZATION OF HIGHLY-HLA SENSITIZED PATIENTS AWAITING KIDNEY TRANSPLANT (NCT03380962). Transplantation 104(S3):p S104-S105, September 2020; see PTO-892 of 10/24/2024).
In view of the cancelation of claim 21 in the reply of 08/20/2025, this rejection is withdrawn.
Previous rejection, withdrawn: claims 22 - 23 were rejected under 35 U.S.C. 103 as being unpatentable over REEVES in view of ABBOUD as applied to claims 1 – 2, 5 – 6, 10 – 11, and 25 – 27 and further in view of VO 2 (Vo, A. et al. A Phase I/II Trial of Tocilizumab (Anti-IL-6 Receptor) + Intravenous Immunoglobulin (IVIG) for Desensitization (DES) in Difficult to DES Patients.: Abstract# 1456. Transplantation 98():p 103, July 15, 2014; see PTO-892 of 10/24/2024).
In view of the cancelation of claims 22 – 23 in the reply of 08/20/2025, this rejection is withdrawn.
Previous rejection, withdrawn: claim 24 was rejected under 35 U.S.C. 103 as being unpatentable over REEVES in view of ABBOUD as applied to claims 1 – 2, 5 – 6, 10 – 11, and 25 – 27 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).
In view of the cancelation of claim 24 in the reply of 08/20/2025, this rejection is withdrawn.
New rejection, necessitated by claim amendments: claims 28, 31 – 33 and 36 – 38 are rejected under 35 U.S.C. 103 as being unpatentable over REEVES in view of ABBOUD.
The present application is drawn to a method for inhibiting cytomegalovirus (CMV) reactivation in a human subject, 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 elevatedIL-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. However, ABBOUD teaches the administration of an IL-6 inhibitor 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. 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.
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.
New rejection, necessitated by amendment: 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.
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, 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.
New rejection, necessitated by amendments: 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.
The teachings of REEVES, ABBOUD, and KENNEDY are presented above and are incorporated herein.
JASKULA is directed to CMV donor/recipient serostatus 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.
New rejection, necessitated by claim amendments: 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.
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 and 35, 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.
Response to Arguments
On page 6 of the reply of 08/20/2025, applicant argues that “1. The Rejections were Legally Deficient and Did Not Establish Prima Facie Obviousness” and “(2) The Combination of Reeves and Abboud does not Teach or Suggest each Pending Claim Element”.
Applicant highlights the limitations “based on the determining, selecting a therapeutically effective amount of a dose of a an IL-6 inhibitor” of present claim 28. However, each of the cited references teach doses of an IL-6 inhibitor applied to cells or administered to patients and thus, the cited references read on this limitation.
Furthermore, determining and selecting a therapeutically effective amount are routine steps in the art. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of Americav.Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)”. See MPEP 2144.05 (I) and (II).
Because REEVES teaches a method for inhibiting cytomegalovirus (CMV) reactivation by administering a therapeutically effective amount of a dose of an IL-6 inhibitor and suggests that the method may be used in transplant patients, as discussed above, and ABBOUD teaches the use of IL-6 inhibitors in human subjects as discussed above, it would have been obvious to administer an IL-6 inhibitor to a human subject to inhibit CMV reactivation. There would have been a reasonable expectation of success considering that an IL-6 inhibitor has been shown to be effective at inhibiting CMV reactivation and safe to use in humans as evidenced by the applied art.
On page 8 of the reply of 08/20/2025, applicant argues that “3. Factual Statements Underlying the Rejections based on Abboud are Incorrect. The Office's 35 U.S.C. § 103 rejections based on Reeves and Abboud rely on the statement that Abboud discloses administration of tocilizumab to the same population of patients as instantly claimed. OA, p. 6. However, according to the properly filed and attested to Expert Declaration pursuant to CFR 1.132 submitted to the Office on January 27, 2025, Dr.
Degli-Esposti explained that "[t]his statement is incorrect." Declaration, paragraph 12 (emphasis added). According to the January 27, 2025 Expert Declaration, "[p]atients with cytokine release syndrome (CRS) have a distinct, IL-6 mediated inflammatory syndrome after transplant that is distinct from GVHD and unrelated to cytomegalovirus reactivation." However, as previously discussed of record, ABBOUD is cited to show that the use of IL-6 inhibitors, specifically Applicant’s claimed tocilizumab, is safe to administer to humans, specifically transplant patients. Although, ABBOUD discusses the effect of tocilizumab on CRS and not CMV reactivation, ABBOUD teaches the mechanism of IL-6.
REEVES in view of ABBOUD show how HCMV and CRS share similarities in mechanism. REEVES teaches that “ [c]linically, HCMV reactivation occurs in highly inflammatory environments (i.e., transplantation); thus, the implications of this study could potentially provide novel approaches for therapeutic intervention” (see abstract), and ABBOUD teaches that “CRS is characterized by high levels of inflammatory cytokines, including IL-6” (see p. 1852, left column, second paragraph).” Thus, one having ordinary skill in the art would recognize that the cause of both HCMV and CRS is inflammation, specifically inflammation caused by IL-6, and inhibiting IL-6 in either HCMV or CRS would alleviate either disorder.
On page 8, last paragraph of the reply, applicant discusses the Degli-Esposti Declaration of 08/20/2025. The Degli-Esposti Declaration is insufficient to overcome the rejection of the present claims under 35 USC 103 because, regarding points 9 and 10, although REEVES uses a myeloid cell model and discusses the implications of HCMV with regard to DC differentiation, REEVES clearly implicates IL-6 in CMV reactivation and clearly points out IL-6 inhibition abrogates CMV reactivation. REEVES further states that the finding that IL-6 inhibition has significant clinical implications in CMV treatment (see Conclusions).
Regarding points 11 and 12 of the declaration, although REEVES states that other factors may contribute to HCMV reactivation in vivo, REEVES focuses on IL-6 and thus it would have been obvious to start at IL-6 when determining treatments for CMV reactivation on humans.
Regarding point 13 of the declaration, although REEVES’ findings were a result of human cell culture experiments, REEVES teaches 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 in mature myeloid cells” (see introduction, first paragraph), and REEVES teaches that IL-6 is a major trigger. Thus, it would have been obvious to focus on IL-6 and its inhibition in the treatment of CMV reactivation in humans.
Regarding points 14 and 15, although these points may be true, REEVES never taught that the in vitro data cannot resemble a physiological or clinical setting. Rather REEVES expressly states that “the modulation of IL-6 could have important implications for future therapeutic strategies.” See last sentence of Conclusions.
Furthermore, regarding point 16, REEVES mentions that “HCMV seropositivity and elevated IL-6 levels have been suggested to be a predictor of cardiac disease (2) and are associated with increased risk for inflammatory bowel diseases (30) as well as with disease following bone marrow transplantation” (see Conclusions) which suggests that the result of IL-6 inhibitor on CMV reactivation has implications in bone marrow transplantation in CMV-seropositive patients. Thus, although REEVES discloses the results of in vitro experiments, REEVES teaches that the results may have clinical implications.
Regarding points 17 – 20, as discussed in the 103 rejection above, ABBOUD discloses the use of IL-6 inhibitor tocilizumab in patients that are CMV-seropositive, rendering the use of an IL-6 inhibitor, such as tocilizumab, in humans, obvious.
Regarding points 21 and 22 of the declaration, REEVES and ABBOUD both teach the reduction of IL-6-related disorders with an IL-6 inhibitor. Both REEVES and ABBOUD teach that transplantation can elevate IL-6 levels. Thus, REEVES in view of ABBOUD render the present application obvious.
Regarding points 23 – 25, 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.
Regarding point 26, JORDAN alone does not render the present claims 34 – 35 and 43 – 44 obvious but REEVES in view of ABBOUD and further in view of JORDAN. REEVES in view of ABBOUD and further in view of JORDAN renders the limitations of present claims 34 – 35 and 43 – 44 obvious for the reasons discussed above.
On page 9 of the reply of 08/20/2025, applicant argues that “[i]n contrast, the patient population of the pending claims are selected based on an upcoming bone marrow or stem cell transplant and a CMV seropositive serological status. At the time of IL-6 inhibitor administration for the patient group of the claims, the patients do not have an IL-6 mediated inflammatory syndrome following a transplant to inhibit. As such, they are clearly not the "same population of patients." Current Declaration, paragraphs 18-20 (emphasis in original).” However, REEVES teaches that “[a] key criterion of latency is the ability to reenter the lytic phase of infection (reactivation) . . . HCMV reactivation and disease occur in highly inflammatory environments (23, 32)(i.e., transplantation); thus, there is a correlative link between the two events.” Furthermore, REEVES teaches that “evident from these studies was that IL-6 was a key component of HCMV reactivation from potentially permissive cells” (see Conclusions). Thus REEVES teaches that transplantation causes inflammation which can cause HCMV reactivation where the HCMV can change from a dormant latent phase to the dangerous lytic phase. Therefore, because REEVES teaches that HCMV reactivation is caused by dormant HCMV entering the lytic phase when IL-6 becomes elevated during transplantation, it would have been obvious to administer an IL-6 inhibitor to patients prior to transplantation to patients when HCMV will likely be in the lytic phase.
On page 13, of the reply of 08/20/2025, applicant argues that “4. There is No Reasonable Expectation of Success The current Expert Declaration submitted with this Office Action Response describes numerous reasons why there would be no reasonable expectation of success to arrive at the claimed invention based on the combined teachings of Reeves and Abboud. The myriad reasons are not reproduced here in full, but instead the following excerpts including quotations from Reeves are provided to highlight that even Reeves explained the deficiencies and shortcomings of this work when contemplating a transition to clinical work in humans: Reactivation of viral gene expression involves a wide range of inflammatory signals that rnay or may not be involved in hurnan reactivation. Acknowledging the stark differences between the system utilized by Reeves and the in vivo environment, Reeves stated, [o]f note is the apparent ease and rapidity with which HCMV reactivates in vivo compared what that seen in experimental and natural latency analyses in vitro, suggesting that further undefined stimuli which are clearly absent in experimental models must play a role in efficient reactivation.”
Applicant’s argument is not persuasive because the cited references all have IL-6 and the use of IL-6 inhibitors, such as the claimed tocilizumab, to treat immune-related issues that can arise with transplant patients. The cited references teach that IL-6 is an inflammatory cytokine that causes adverse effects on transplant patients and that an IL-6 inhibitor can alleviate those adverse effects. REEVES teaches that the adverse effect is CMV reactivation and “the interception of IL-6 signaling with biological inhibitors significantly abrogated HCMV reactivation” (see abstract) and teaches that IL-6 inhibitors may have therapeutic implications for transplantation as discussed above. Thus, the cited references renders a method of inhibiting CMV reactivation obvious.
On pages 20 – 21 of the reply of 08/20/2025, applicant argues that “Jaksula Does Not Remedy the Deficiencies of Reeves.” Applicant’s argument is not persuasive because REEVES, and the other cited references render the present claims obvious as discussed in the 103 rejection and response to the reply and declaration of 08/20/2025 above.
Conclusion
Claims 28 – 47 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ESTELLA M. GUSTILO whose telephone number is (703)756-1706. The examiner can normally be reached Monday - Friday 9:00 AM - 5:00 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JANET L. EPPS-SMITH can be reached at 571-272-0757. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ESTELLA M. GUSTILO/Examiner, Art Unit 1646
/PETER J REDDIG/Primary Examiner, Art Unit 1646