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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Applicant cannot rely upon the certified copy of the foreign priority application to overcome the rejection set forth in view of Mouton et al. because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
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 17 and 20 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.
Claims 17 and 20 recite “the reference proliferative capacity of the T cells” and this phrase lacks antecedent basis in claim 9 which does not recite or refer to a reference proliferative capacity.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-14 and 16-22 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and a judicial exception without significantly more. The claim(s) recite(s) “determining the proliferative capacity,” “comparing the TTV load measured in a) with a reference TTV load,” “comparing the proliferative capacity of the T-cells measured in a) with a reference proliferative capacity of the T cells,” “determining a change in activity of the T cells,” “comparing the TTV viral loads,” “determining the change in the patient’s TTV load,” “determining susceptibility to microbial infections,” and “determining susceptibility to graft-versus-host disease” which are all steps that can be practiced in the mind and are mental process judicial exceptions. Furthermore, the claims set forth the relationship between torque teno virus load in a biological sample and the proliferated capacity of the cells in a subject, as well as the relationship between proliferation capacity and risk for microbial infection and graft-versus-host disease which are a naturally occurring relationships and are law of nature judicial exceptions.
This judicial exception is not integrated into a practical application because the claims do not recite or use the judicial exceptions in any way. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the step in addition to the judicial exception (i.e. “measuring a Torque Teno Virus” load from a biological sample) is recited at an extremely high level of generality and employs techniques which were well established at the time of filing such as amplification, sequencing or hybridization. See specification p. 16 which teaches that commercial diagnostic kit was available for measuring TTV load by amplification, and paragraph 59-65 which list many techniques that were well known and readily available for a person skilled in the art (see especially paragraph 59).
Claim Rejections - 35 USC § 102
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.
Claim(s) 9, 16, 17, and 20 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pradier et al. (Front. Immunol. 11:998; 13 pages).
Pradier teaches obtaining peripheral blood samples from hematopoietic stem cell transplantation (HSCT) patients on days 0, 50, 100, 150, 200, 300, 400, and 547 and 2 to 9 years post-HSCT (p. 2, Col. 1). Torque teno virus (TTV) in plasma was quantified using a real-time PCR assay (p. 3, Col. 1).
Thus, with regard to step (a), the reference teaches determining a TTV viral load from a biological sample taken from the patient at a first time point and, with regard to step (b) at a second time point later than the first time point in step (a). See Results and figure 1. The reference teaches comparing the TTV viral loads measured in (a) and (b), and determining a change in the patient’s TTV load. See Results and Figure 1, for example.
Regarding claim 16, the HSCT was allo-HSCT (title and throughout).
Regarding claim 17, this claim is indefinite, but insofar as it simply states an inherent property the claim is anticipated.
Regarding claim 20, the reference teaches comparing TTV load at multiple time points.
Claim Rejections - 35 USC § 103
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.
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.
Claim(s) 1-7, 10-11, 12, 18, and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Mouton et al. (Viruses 2020, 12, 1292; doi:10.3390/v12111292; 11 pages; Published 11 November 2020).
The reference teaches that a correlation was observed between viral load and T-cell proliferation capacity (abstract, figure 2b, p. 6 2nd full sentence). The reference teaches TTV could interesting as a biomarker to estimate immune function and finally to predict infections and/or clinical events related to the immune system.
The reference teaches detecting TTV viral load by qPCR (figure 1 description).
The reference teaches that the sample is serum.
The reference suggests but does not carry out a step of determining the proliferative capacity of T cells in view of a measured viral load.
The reference provides a series of “reference values” of proliferation potential and their corresponding TVV levels in Figure 2b.
The reference teaches the subjects have had allogeneic–hematopoietic–stem-cell transplantation.
The reference teaches patients that have undergone myeloablative or attenuated conditioning before transplantation (Table 1).
It would have been obvious to have modified the methods taught by Mouton et al. so as to have applied the correlation noted by the reference between viral load and T-cell proliferation to a patient sample and measure viral load of TTV in a sample and then predict the proliferative capacity of T-cells. This would have been obvious because the reference specifically suggests that TTV could be an interesting biomarker to estimate immune function. Furthermore, it would have been obvious to make the prediction about proliferative potential by referring the reference values given in Figure 2 of the reference. Furthermore, following the teachings of Mouton et al. it would have been obvious to have predicted immune susceptibility to microbial infections and to GVHD based on the proliferation potential determined based on TTV viral load. To do so would have been obvious because the reference explicitly suggests using these data to predict infections and clinical events related to the immune system. The reference teaches that monitoring of TTV viraemia could be a fast suitable option to objectively assess the competence of immune function in at risk populations, and the reference teaches that a rapid and individual assessment of the immune system’s capacities could be of clinical interest to adapt anti-infectious prophylactic treatments and treatments to prevent graft rejection, which are among the amin causes of morbimortality in the allogeneic–haematopoietic–stem-cell transplantation population (p. 5, conclusions).
Claim(s) 1-7, 9, 17, and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Focosi et al., Maggi F et al. (Transplantation 2008; 85: 1867), and Brenchley et al. (Blood, 1 April 2003, Volume 101, Number 7).
Focosi et al. teach that TTV viremia increased parallel to the increase of circulating CD8+CD57+ lymphocytes, which are known to be an indirect marker of functional immune deficiency. The kinetics of TTV viremia correlated with both the absolute number and the percentage of CD8+57+ T lymphocytes (Figures 1C, 2, and 3).
Fosoci et al. teach obtaining peripheral blood samples from HSCT patients on days at multiple time points before and post-HSCT (see 3.1). Torque teno virus (TTV) in plasma was quantified using a real-time PCR assay (see 3.2).
Fosoci et al. suggest that monitoring TTV plasma levels over time may help predict the likelihood of infectious complications and the duration of antimicrobial prophylaxis (section 5).
Thus, with regard to step (a) of claim 1 and 9 the reference teaches determining a TTV viral load from a biological sample taken from the patient at a first time point and,
Additionally with regard to claims with regard to step (b) of claims 8 and 9, at a second time point later than the first time point in step (a). See Table 1 and figure 1.
The reference teaches comparing the TTV viral loads measured in (a) and (b), and determining a change in the patient’s TTV load. See Table 1 and Figure 1, for example.
Regarding claim 2, the TTV load was measured by amplification (see 3.2).
Regarding claim 3, the biological sample was plasma (see 3.2).
Regarding claims 4, 17, and 20 reference values for TTV relative to CD8+57+cells are given in Figures 3A and B. Reference values include values for the proliferative capacity (i.e. the level of CD8+57+ cells) of immunosuppressed individuals. The reference also teaches comparing the value of individuals at different time points, see Table 1. Furthermore, the reference teaches that for an individual, once the basal peaks is known, it becomes possible to extrapolate the time to when TVV levels will return to basal value (Section 5; Figure 4).
Regarding claims 5, 6, the subjects have received HSCT. See throughout.
Regarding claim 7, the patients received myeloablative or attenuated conditioning (melphalan and granulocyte colony stimulating factor or BEAM polychemotherapy and G-CSF). See 3.1.
Regarding claim 17, this claim is indefinite, but insofar as it simply states an inherent property the claim is anticipated.
Regarding claim 20, the reference teaches comparing TTV load at multiple time points.
Similarly, Maggi et al. teach that TTV load and percent CD8+57+ cells correlated over time, providing a demonstration of a temporal correlation between the size of a TTV chronic viremia and circulating CD8+57+ lymphocytes. The reference suggests that TTV viremia might be exploited to obtain a functional assessment of the immune status in HSCT recipients.
Fosoci and Maggi do not teach determining the proliferative potential of t-cells in the sample based on the TTV load, as required by claims 1, 8, 10, and 12.
Brenchley et al. teach that expression of CD57 in CD8-Tcells defines replicative senescence. That is, as CD57 expression goes up, the proliferation potential of the cells goes down (p. 2711, title, abstract, 2nd column).
Thus, it would have been prima facie obvious to have modified the methods taught by Fosoci and Maggi so as to have predicted that as the TTV load increases, the proliferative potential of T-cells cells decreases, since there is an increase of CD8+57+ cells and expression of CD57 defines inability of the cells to proliferate. Therefore, it follows that as the percentage of CD8+57+ T cells in a T cell population increases, the proliferation potential of the T-cell population decreases.
With regard to claims that set forth particular references to use for determining the proliferation potential, Fosoci teaches reference values for TTV relative to CD8+57+cells in Figures 3A and B. Reference values include values for the proliferative capacity (i.e. the level of CD8+57+ cells) of immunosuppressed individuals. The reference also teaches comparing the value of individuals at different time points, see Table 1. Furthermore, the reference teaches that for an individual, once the basal peaks is known, it becomes possible to extrapolate the time to when TVV levels will return to basal value (Section 5; Figure 4). It would have been well within the ordinary skill to have optimized the assay for predicting proliferation potential by selecting appropriate relevant reference values from the different options provided in the prior art.
Claim(s) 1-14 and 16-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Foscoci, Maggi, and Brenchley as applied to claims 1-7, 9, 17, and 20 above, and further in view of Pradier et al.
The teachings of Foscoci, Maggi, and Brenchley are given previously in this Office action and are fully incorporated here. These do not teach a method wherein the patient has had an allogenic hematopoietic stem cell transplantation. The references also do not teach determining the susceptibility to microbial infections or graft versus host disease.
Pradier teaches obtaining peripheral blood samples from hematopoietic stem cell transplantation (HSCT) patients on days 0, 50, 100, 150, 200, 300, 400, and 547 and 2 to 9 years post-HSCT (p. 2, Col. 1). Torque teno virus (TTV) in plasma was quantified using a real-time PCR assay (p. 3, Col. 1). The reference teaches that in these patients TTV titers peaked at 100 days post-transplant and that higher titers after 100 days were associated with worse overall survival and higher risk of GVHD and infections (viral infections (see abstract and p. 8).
It would have been prima facie obvious to have modified the method taught by Foscoci, Maggi and Brenchley so as to have also applied it to patients who had allo-HSCT. One would have been motivated to do so in order to provide an additional tool for predicting outcome to allo-HSCT and guiding treatments. One would have been motivated to use proliferative capacity of T-cells, a measure of functional immunity, to predict microbial infections and GVHD in order to provide an additional tool for guiding doctors as to when to apply appropriate treatments or preventatives.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/ Primary Examiner, Art Unit 1682