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 .
DETAILED ACTION
Election of Species and Status of the Claims
Claims 32-36, 40, 42-47, and 52-61 are pending. Claims 54-61 are withdrawn from further consideration as being directed towards nonelected species until a generic claim has been found allowable. Claims 32-36, 40, 42-47, and 52-53 are examined on their merits.
35 U.S.C. § 103 Rejections Maintained
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 rejection of claims 32-36, 40, 42-47, and 52-53 under 35 U.S.C. 103 as being unpatentable over Azevedo (Azevedo et al., Cytomegalovirus infection in transplant recipients. Clinics (Sao Paulo). 2015 Jul;70(7):515-23) in view of Makwana (Makwana et al., (2017), CMV drives the expansion of highly functional memory T cells expressing NK-cell receptors in renal transplant recipients. Eur. J. Immunol., 47: 1324-1334) is maintained.
Applicant’s arguments in the response filed on October 15th 2025 are acknowledged. Applicant argues that the combination of Azevedo and Makwana does not render the claims (i.e. the treatment of a CMV infection identified as lacking elevated KLRG1+/CD8+ levels) obvious, because one of ordinary skill in the art would expect a CMV-infected patient to have elevated KLRG1+/CD8+ levels. Applicant’s arguments are found not persuasive.
The up-regulation of KLRG1 and CD8+ T-cells, as described by Makwana, is not disputed. However, this up-regulation is described by Makwana as being a long-term effect.
“Memory CD8+ T cells can upregulate the expression of NK-cell receptors following repeated exposure to antigen.”
[Makwana, pg. 1327]
Makwana further teaches that this up-regulation can continue for years:
“The data show that latent and active CMV infection can alter T-cell subsets in RTRs many years after transplantation, and up-regulate T-cell expression of NK-cell receptors.”
[Makwana, pg. 1324]
That is, over time, as a CMV-infected subject receives greater exposure to the CMV antigen, the up-regulation of KLRG1/CD8+ T cells would be expected to increase the detected level of KLRG1+/CD8+.
With this knowledge, one of ordinary skill in the art would reasonably expect the patient population described by applicant, that is, a subject who is the recipient of a donor-positive/recipient negative transplant (i.e. is seronegative at the time of transplant) and is CMV positive, would still be expected to have the lack of elevated KLRG1+/CD8+ levels, especially as CMV infection is typically found within the first few months following transplantation. See Azevedo:
“Cytomegalovirus infection is a frequent complication after transplantation. This infection occurs due to transmission from the transplanted organ, due to reactivation of latent infection, or after a primary infection in seronegative patients and can be defined as follows: latent infection, active infection, viral syndrome or invasive disease. This condition occurs mainly between 30 and 90 days after transplantation. In hematopoietic stem cell transplantation in particular, infection usually occurs within the first 30 days after transplantation and in the presence of graft-versus-host disease. The major risk factors are when the recipient is cytomegalovirus seronegative and the donor is seropositive as well as when lymphocyte-depleting antibodies are used.”
[Azevedo, pg. 515]
Furthermore, Azevedo describes the donor-positive/recipient negative transplant recipient as high-risk:
“In solid organ transplantation (SOT), the greatest risk factor for CMV disease is a serological mismatch between the donor and the recipient (the recipient is CMV seronegative and the donor is seropositive).”
[Azevedo, pg. 516]
This category of patients would therefore be the one wherein physicians would be most likely to watch out for the infection and thus provide treatment at the first available opportunity.
As one of ordinary skill in the art would reasonably expect
the donor-positive/recipient negative transplant recipient to lack elevated KLRG1+/CD8+ levels at time of CMV infection
the donor-positive/recipient negative transplant recipient to be in the “high-risk” category for infection (i.e. the category of patients in which infection is likely, and thus watched for)
the administration of valganciclovir to be used as a first-line treatment upon discovery of the CMV infection
applicant’s method of treatment is prima facie obvious and the 103 rejections for claims 32-36, 40, 42-47, and 52-53 are maintained.
35 U.S.C. § 103 Rejections Reiterated
Claims 32-36, 40, 42-47, and 52-53 are directed towards a method of treating a cytomegalovirus (CMV) infection in a human donor positive/recipient negative transplant recipient lacking an elevated level of KLRG1+/CD8+ T cells wherein the infection is pre-acute, acute/primary, contraction phase, or chronic CMV infection, via administration of valganciclovir.
Azevedo teaches the treatment of cytomegalovirus in high-risk transplant patients via administration of valganciclovir or its metabolite, ganciclovir:
“Cytomegalovirus disease can be prevented by prophylaxis (the administration of antiviral drugs to all or to a subgroup of patients who are at higher risk of viral replication) or by preemptive therapy (the early diagnosis of viral replication before development of the disease and prescription of antiviral treatment to prevent the appearance of clinical disease). The drug used is intravenous or oral ganciclovir; oral valganciclovir; or, less frequently, valacyclovir. Prophylaxis should continue for 90 to 180 days. Treatment is always indicated in cytomegalovirus disease, and the gold-standard drug is intravenous ganciclovir. Treatment should be given for 2 to 3 weeks and should be continued for an additional 7 days after the first negative result for viremia.”
[Azevedo, pg. 515, Abstract]
Azevedo further defines the high-risk population as when the donor is seropositive and the recipient is seronegative (i.e. human donor positive/recipient negative) (Azevedo, Abstract), and states that the treatment option is available for primary CMV infection (Azevedo, Abstract).
Azevedo does not explicitly teach a patient population with the phenotype lacking an elevated level of KLRG1+/CD8+ T cells. However, one of ordinary skill in the art would have a reasonable expectation of success in administering valganciclovir to the population with such a phenotype, because this phenotype would be expected in the seronegative recipient. See Makwana, who teaches that CMV up-regulates KLRG1 and CD8+ T-cells (Makwana, pg. 1327). One of ordinary skill in the art would recognize that the seropositive donor would be expected to have elevated KLRG1+/CD8+ T cell levels, while the seronegative recipient would be expected to be lacking such elevated levels. One of ordinary skill in the art would therefore have a reasonable expectation of success in treating CMV infection in a human donor positive/recipient negative transplant recipient lacking an elevated level of KLRG1+/CD8+ T cells wherein the infection is a primary infection, and claims 32-36, 40, 42-47, and 52-53 are therefore prima facie obvious.
Conclusion
THIS ACTION IS MADE FINAL. 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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/A.J.S./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629