DETAILED ACTION
Status of Claims
Claims 28, 30-55, 58-60, 62, and 65 are pending. Claims 28, 30-36, 48, 53-55, 58-60, and 62 have been amended. Claims 28, 30-55, 58-60, 62, and 65 are under examination.
Withdrawn Claim Objections and/or Rejections
The rejection of claims 28-65 under 35 USC 101 as being directed towards a judicial exception as set forth on pp. 2-11 of the previous office action (mailed on 07/25/2025) has been withdrawn in view of the amended claims (filed on 10/24/2025).
The rejection of claims 57-63 for statutory double patenting over U.S. Patent No. 10100128 as set forth on pp. 30-33 of the previous office action (mailed on 07/25/2025) has been withdrawn in view of the amended claims (filed on 10/24/2025).
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.
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.
Claims 28, 30-34, 36-55, 62, and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Pestano et al., (WO 2009/036427 A2) (IDS filed on 07/21/2022) and in view of Li, Shujing et al. “Serum thymidine kinase 1 is associated with Gleason score of patients with prostate carcinoma.” Oncology letters vol. 16,5 (2018): 6171-6180. doi:10.3892/ol.2018.9345 (IDS filed on 07/21/2022).
Regarding claim 28, Pestano teaches a method for predicting patient survival
comprising: determining a level of thymidine kinase 1 material in a serum sample or a plasma sample (see page 2 lines 1-3) from a patient diagnosed with prostate cancer using an Enzyme-Linked Immunosorbent Assay (ELISA) kit (see page 41 lines 1-4 “Kd values can, for example, be determined by competitive ELISA (enzyme-linked immunosorbent assay) …”) comprising:
a first monoclonal antibody or a first fragment thereof having specificity for an epitope selected from the group consisting of: GEAVAARKLF (SEQ ID NO: 1) of human TK1;at least one of NCPVPGKPGE (SEQ ID NO: 2), PVPGKPGEAV (SEQ ID NO: 3) and NCPVPGKPGEAV (SEQ ID NO: 4) of human TK1; and a conformation dependent epitope of human TK1; and a second monoclonal antibody or a second fragment thereof having specificity for an epitope selected from the group consisting of: GEAVAARKLF (SEQ ID NO: 1) of human TK1; at least one of NCPVPGKPGE (SEQ ID NO: 2), PVPGKPGEAV (SEQ ID NO: 3) and NCPVPGKPGEAV (SEQ ID NO: 4) of human TK1; and a conformation dependent epitope of human TK1 (see SEQ ID NO: 6 of Pestano); and predicting survival of the patient based on the determined level of TK1 protein material in the serum sample or the plasma sample (see page 4 lines 11-21 “Disclosed herein are gene signatures of prostate cancer recurrence, characterized at least in part by altered (e.g., increased or decreased) expression of one or more genes listed in Table 8, which characterizes prostate cancer in subjects afflicted with the disease. For example, gene
expression of wingless-type MMTV integration site family member 5 (WNT5A), thymidine kinase
1 (TK1), and growth arrest specific gene 1 ([GAS]) and/or any other gene listed in Table 8 can
be used to forecast prostate cancer outcome, e.g., disease recurrence or non-recurrence in
patients who have (or are candidates for) prostatectomy. In particular examples, overexpression
of WNT5A and TK1 and down-regulation of GAS] indicates an increased likelihood that the
prostate cancer will recur, and thus a poor prognosis.”), and selecting an anti-cancer treatment for the patient based on the predicted survival of the patient, wherein the anti-cancer treatment is selected from the group consisting of prostatectomy, radiation therapy, and androgen deprivation therapy (ADT) (see page 18 lines 9-13, see page 2 lines 22-25 “Treatment options for more aggressive cancers include radical prostatectomy and/or radiation therapy. Androgen-depletion therapy (such as, gonadotropin-releasing hormone agonists (e.g., leuprolide, goserelin, etc.) and/or bilateral orchiectomy) is also used, alone or in conjunction with surgery or radiation”). While Pestano teaches that serum levels are taken and measured for those being tested for prostate cancer (see page 2 lines 1-3), Pestano does not explicitly state that the TK1 is from serum.
Li teaches serum TK1 (STK1) is a known biomarker for prostate cancer (see abstract).
One of ordinary skill in the art would have been motivated to combine Pestano’s
methods of predicting patient survival with serum TK1 as taught by Li, since Li teaches that
these limitations are beneficial because STK1 is known to be significantly higher in patients with
benign prostatic hyperplasia (BPH) and prostate cancer compared to healthy individuals, and
since STK1 concentration is associated with Gleason scores, it may reduce the number of
biopsies obtained from men with suspected prostate BPH/malignancy by determining STK1
concentration (see page 6178).
Regarding claim 30, Pestano teaches wherein determining the concentration of TK1 protein material in the serum sample or the plasma sample comprises: contacting the serum sample or the plasma sample with the first or second monoclonal antibodies or the fragments
thereof; and measuring an amount of the second monoclonal antibody or the second fragment thereof bound to the TK1 protein material (see pages 8-9 under “Contact” and “Detect”).
While Pestano teaches that serum levels are taken and measured for those being tested
for prostate cancer (see page 2 lines 1-3), Pestano does not explicitly state that the TK1 is from
serum.
Li teaches serum TK1 (STK1) is a known biomarker for prostate cancer (see abstract).
One of ordinary skill in the art would have been motivated to combine Pestano’s
methods of predicting patient survival with serum TK1 as taught by Li, since Li teaches that
these limitations are beneficial because STK1 is known to be significantly higher in patients with
benign prostatic hyperplasia (BPH) and prostate cancer compared to healthy individuals, and since STK1 concentration is associated with Gleason scores, it may reduce the number of
biopsies obtained from men with suspected prostate BPH/malignancy by determining STK1
concentration (see page 6178).
Regarding claim 31, Pestano teaches correlating the measured amount of antibody or
fragment thereof bound to the TK1 material to a level of TK1 material (see page 9 lines 15-20
“For example, use of an antibody specific for a particular protein (e.g., WNT5A, TKI or GASI)
permits detection of the of the protein or protein-protein interaction in a sample, such as a
sample containing prostate cancer tissue. In another example, use of a probe or primer specific
for a particular gene (e.g., WNT5A, TKJ or GAS]) permits detection of the of the desired nucleic
acid molecule in a sample, such as a sample containing prostate cancer tissue.”, see page 29 lines 28-31 teaching the use of a second antibody, see page 35 lines 1-8 “A difference in the level of a target protein in the sample (e.g., WNT5A, TKI and GAS 1), relative to the level of the same target protein found an analogous sample from a subject who has not had a recurring prostate cancer, in particular examples indicates that the subject has a poor prognosis.”).
While Pestano teaches that serum levels are taken and measured for those being tested
for prostate cancer (see page 2 lines 1-3), Pestano does not explicitly state that the TK1 is from
serum.
Li teaches serum TK1 (STK1) is a known biomarker for prostate cancer (see abstract).
One of ordinary skill in the art would have been motivated to combine Pestano’s
methods of predicting patient survival with serum TK1 as taught by Li, since Li teaches that
these limitations are beneficial because STK1 is known to be significantly higher in patients with
benign prostatic hyperplasia (BPH) and prostate cancer compared to healthy individuals, and
since STK1 concentration is associated with Gleason scores, it may reduce the number of
biopsies obtained from men with suspected prostate BPH/malignancy by determining STK1
concentration (see page 6178).
Regarding claim 32, Pestano teaches correlating the measured amount of the second monoclonal antibody or the second fragment comprises correlating the measured amount of the second antibody or the second fragment thereof to a concentration of TK1 protein material using a pre-defined correlation between measured amount of the second antibody or the second fragment thereof bound to recombinant human TK1 and a concentration of recombinant human
TK1 (See claim 1, see page 34 lines 27-31 and page 35 lines 1-8 disclosing the following.
“The proteins or antibodies forming the array can be directly linked to the support. Alternatively,
the proteins or antibodies can be attached to the support by spacers or linkers to the solid
support. Changes in protein expression can be detected using, for instance, a protein -specific
binding agent, which in some instances is labeled. In certain examples, detecting a change in
protein expression includes contacting a protein sample obtained from a prostate cancer sample
of a subject with a protein-specific binding agent (which can be for example present on an
array); and detecting whether the binding agent is bound by the sample and thereby measuring
the levels of the target protein present in the sample. A difference in the level of a target protein
in the sample (e.g., WNT5A, TKI and GAS 1), relative to the level of the same target protein
found an analogous sample from a subject who has not had a recurring prostate cancer, in
particular examples indicates that the subject has a poor prognosis.” See page 38 lines 15-16
disclosing: “Specific binding reagents include, for example, antibodies or functional fragments or
recombinant derivatives thereof.”. See page 11 lines 9-27 under “Specific binding (or
obvious derivations of such phase, such as specifically binds, specific for, etc)”.
While Pestano teaches that serum levels are taken and measured for those being tested
for prostate cancer (see page 2 lines 1-3), Pestano does not explicitly state that the TK1 is from
serum.
Li teaches serum TK1 (STK1) is a known biomarker for prostate cancer (see abstract).
One of ordinary skill in the art would have been motivated to combine Pestano’s
methods of predicting patient survival with serum TK1 as taught by Li, since Li teaches that
these limitations are beneficial because STK1 is known to be significantly higher in patients with benign prostatic hyperplasia (BPH) and prostate cancer compared to healthy individuals, and
since STK1 concentration is associated with Gleason scores, it may reduce the number of
biopsies obtained from men with suspected prostate BPH/malignancy by determining STK1
concentration (see page 6178).
Regarding claim 33, Pestano teaches wherein determining the concentration of TK1 protein material comprises determining, using the ELISA kit, the concentration of TK1 protein material in the serum sample or the plasma sample taken from the patient in connection with diagnosing the patient with prostate cancer (see claim 1, claim 15, abstract, see page 40 lines 23-31 and page 41 lines 1-5).
While Pestano teaches that serum levels are taken and measured for those being tested
for prostate cancer (see page 2 lines 1-3), Pestano does not explicitly state that the TK1 is from
serum.
Li teaches serum TK1 (STK1) is a known biomarker for prostate cancer (see abstract).
One of ordinary skill in the art would have been motivated to combine Pestano’s
methods of predicting patient survival with serum TK1 as taught by Li, since Li teaches that
these limitations are beneficial because STK1 is known to be significantly higher in patients with
benign prostatic hyperplasia (BPH) and prostate cancer compared to healthy individuals, and
since STK1 concentration is associated with Gleason scores, it may reduce the number of
biopsies obtained from men with suspected prostate BPH/malignancy by determining STK1
concentration (see page 6178).
Regarding claim 34, Pestano teaches wherein determining the concentration of TK1 protein material comprises determining the concentration of TK1 material in the serum sample or the plasma sample from a patient diagnosed with metastatic prostate cancer using the antibody or the fragment thereof specifically binding to the serum form of human TK 1 (see claim 1, claim 15, see page 7 lines 28-30 “Cancer: Malignant neoplasm, for example one that has undergone characteristic anaplasia with loss of differentiation, increased rate of growth, invasion of surrounding tissue, and is capable of
metastasis.”).
While Pestano teaches that serum levels are taken and measured for those being tested
for prostate cancer (see page 2 lines 1-3), Pestano does not explicitly state that the TK1 is from
serum.
Li teaches serum TK1 (STK1) is a known biomarker for prostate cancer (see abstract).
One of ordinary skill in the art would have been motivated to combine Pestano’s
methods of predicting patient survival with serum TK1 as taught by Li, since Li teaches that
these limitations are beneficial because STK1 is known to be significantly higher in patients with
benign prostatic hyperplasia (BPH) and prostate cancer compared to healthy individuals, and
since STK1 concentration is associated with Gleason scores, it may reduce the number of
biopsies obtained from men with suspected prostate BPH/malignancy by determining STK1
concentration (see page 6178).
Regarding claims 36 and 48, Pestano teaches comprising comparing the determined
concentration of TK1 protein material in the serum sample or the plasma sample with a threshold value, wherein predicting survival of the patient comprises predicting poor survival of the patient if the determined concentration of TK1 protein material in the serum sample or the plasma sample exceeds the threshold value and otherwise predicting good survival of the patient (see page 4 lines 19-24 “In particular examples, overexpression of WNT5A and TKJ and down-regulation of GAS indicates an increased likelihood that the prostate cancer will
recur, and thus a poor prognosis. The disclosed gene signatures may be useful, for example, to
screen prostate cancer patients for cancer recurrence, which can aid prognosis and the making
of therapeutic decisions in prostate cancer.”, see page 69 lines 10-16 “Similarly, if GAS 1, TKl,
and WNT5A expression is similar relative to a value representing GAS 1, TKl, and WNT5A
expression in a recurring cancer, this indicates that the subject has a poor prognosis as the
cancer is likely to recur. If GAS 1, TKl, and WNT5A expression is similar (e.g., no more than a
2-fold difference) relative to a value representing GASl, TKl, and WNT5A expression in a non - recurring cancer, this indicates that the subject has a good prognosis as the cancer is not likely
to recur.”).
While Pestano teaches that serum levels are taken and measured for those being tested
for prostate cancer (see page 2 lines 1-3), Pestano does not explicitly state that the TK1 is from
serum.
Li teaches serum TK1 (STK1) is a known biomarker for prostate cancer (see abstract).
One of ordinary skill in the art would have been motivated to combine Pestano’s
methods of predicting patient survival with serum TK1 as taught by Li, since Li teaches that
these limitations are beneficial because STK1 is known to be significantly higher in patients with
benign prostatic hyperplasia (BPH) and prostate cancer compared to healthy individuals, and
since STK1 concentration is associated with Gleason scores, it may reduce the number of
biopsies obtained from men with suspected prostate BPH/malignancy by determining STK1
concentration (see page 6178).
Regarding claims 37-47, 49-52, Pestano and Li don’t explicitly teach the various
threshold value range of instant claims 37-47 and 49-52. However, Pestano teaches methods of
predicting patient survival of prostate cancer using TK1 and Li teaches that serum TK1 is a
known biomarker for prostate cancer. Both Pestano and Li teach the benefits of measuring TK1
in individuals to diagnose prostate cancer such that one of ordinary skill would reasonably use
any threshold value of this biomarker known to be associated with prostate cancer. Where the
general conditions of the claim are taught in the prior art, discovering workable or optimum
range requires routine skills in the art. In this case, the general conditions of the claim are taught
by the prior art, and the recited duration of measurement falls within a workable or optimum
range, and therefore its discovery requires routine skills in the art. Thus, it would have been
prima facie obvious at the time of the instant application to determine the workable or opt imum
threshold range as the discovery requires routine skills in the art.
Regarding claim 53, Pestano teaches determining prostate-specific antigen (PSA) in a
body sample from the patient (see page 1 line 31 and page 2 lines 1-3 “Prostate cancer typically is diagnosed with a digital rectal exam ("DRE") and/or prostate specific antigen (PSA) screening. An abnormal finding on DRE and/or an elevated serum PSA level (e.g., >4 ng/ml)
can indicate the presence of prostate cancer.”), wherein predicting survival of the patient
comprises predicting survival of the patient based on the determined concentration of STK1 protein material in the serum sample or the plasma sample and based on the determined PSA in the body sample (see page 17 lines 5-12 “Other exemplary methods predict the likelihood of prostate progression. Prostate cancer progression means that one or more indices of prostate cancer (e.g., serum PSA levels) show that the disease is advancing independent of treatment. In some examples, prostate cancer progression is marked by rising PSA levels (e.g., greater than 2.0-2.5 ng/mL) and/or by identification of (or increasing numbers of) prostate cancer cells in the blood, prostate biopsy or aspirate, in lymph nodes (e.g., in the pelvis or elsewhere) or at a metastatic site (e.g., muscles that help control urination, the rectum, the wall of the pelvis, in bones or other organs).”, see page 69 lines 10-16 “Similarly, if GAS 1, TKl, and WNT5A expression is similar relative to a value representing GAS 1, TKl, and WNT5A expression in a recurring cancer, this indicates that the subject has a poor prognosis as the cancer is likely to recur. If GAS 1, TKl, and WNT5A expression is similar (e.g., no more than a 2-fold difference) relative to a value representing GASl, TKl, and WNT5A expression in a non-recurring cancer, this indicates that the subject has a good prognosis as the cancer is not likely to recur.”).
While Pestano teaches that serum levels are taken and measured for those being tested
for prostate cancer (see page 2 lines 1-3), Pestano does not explicitly state that the TK1 is from
serum.
Li teaches serum TK1 (STK1) is a known biomarker for prostate cancer (see abstract).
One of ordinary skill in the art would have been motivated to combine Pestano’s
methods of predicting patient survival with serum TK1 as taught by Li, since Li teaches that these limitations are beneficial because STK1 is known to be significantly higher in patients with
benign prostatic hyperplasia (BPH) and prostate cancer compared to healthy individuals, and
since STK1 concentration is associated with Gleason scores, it may reduce the number of
biopsies obtained from men with suspected prostate BPH/malignancy by determining STK1
concentration (see page 6178).
Regarding claim 54, Pestano teaches determining International Society of Urological
Pathology (ISUP) Gleason grade group or Gleason score for the patient, wherein predicting
survival of the patient comprises predicting survival of the patient based on the determined concentration of TK1 protein material in the serum sample or the plasma sample and based on the determined ISUP Gleason grade group or Gleason score (see page 2 lines 20-21 “Men with a 10-year life expectancy or less who have a low Gleason number and whose tumor has not spread beyond the prostate often are not treated.”, see page 47 lines 15-17 “Tissue sections were stained with hematoxylin and eosin ("H&E") using standard (manual) methods to determine Gleason sum scores, tumor volume, location, and pathologic stage.”, see page 69 lines 10-16 “Similarly, if GAS 1, TKl, and WNT5A expression is similar relative to a value representing GAS 1, TKl, and WNT5A expression in a recurring cancer, this indicates that the subject has a poor prognosis as the cancer is likely to recur. If GAS 1, TKl, and WNT5A expression is similar (e.g., no more than a 2-fold difference) relative to a value representing GASl, TKl, and WNT5A expression in a non-recurring cancer, this indicates that the subject has a good prognosis as the cancer is not likely to recur.”).
While Pestano teaches that serum levels are taken and measured for those being tested
for prostate cancer (see page 2 lines 1-3), Pestano does not explicitly state that the TK1 is from
serum.
Li teaches serum TK1 (STK1) is a known biomarker for prostate cancer (see abstract). Li further teaches that STK1 concentrations are associated with Gleason scores (see page
6171).
One of ordinary skill in the art would have been motivated to combine Pestano’s
methods of predicting patient survival with serum TK1 as taught by Li, since Li teaches that
these limitations are beneficial because STK1 is known to be significantly higher in patients with
benign prostatic hyperplasia (BPH) and prostate cancer compared to healthy individuals, and
since STK1 concentration is associated with Gleason scores, it may reduce the number of
biopsies obtained from men with suspected prostate BPH/malignancy by determining STK1
concentration (see page 6178).
Regarding claim 55, Pestano teaches determining prostate-specific antigen (PSA) in a
body sample from the patient, wherein predicting survival of the patient comprises predicting
survival of the patient based on the determined concentration of TK1 protein material in the serum sample or the plasma sample, based on the determined PSA in the body sample (see page 17 “Other exemplary methods predict the likelihood of prostate progression. Prostate cancer progression means that one or more indices of prostate cancer (e.g., serum PSA levels) show that the disease is advancing independent of treatment. In some examples, prostate cancer progression is marked by rising PSA levels (e.g., greater than 2.0-2.5 ng/mL) and/or by identification of (or increasing numbers of) prostate cancer cells in the blood, prostate biopsy or aspirate, in lymph nodes (e.g., in the pelvis or elsewhere) or at a metastatic site (e.g., muscles that help control urination, the rectum, the wall of the pelvis, in bones or other organs).”, see page 69 lines 10-16 “Similarly, if GAS 1, TKl, and WNT5A expression is similar relative to a value representing GAS 1, TKl, and WNT5A expression in a recurring cancer, this indicates that the subject has a poor prognosis as the cancer is likely to recur. If GAS 1, TKl, and WNT5A expression is similar (e.g., no more than a 2-fold difference) relative to a value representing GASl, TKl, and WNT5A expression in a non-recurring cancer, this indicates that the subject has a good prognosis as the cancer is not likely to recur.”) and based on the determined ISUP Gleason grade group or Gleason score (see page 47 lines 15- 17 “Tissue sections were stained with hematoxylin and eosin ("H&E") using standard (manual) methods to determine Gleason sum scores, tumor volume, location, and pathologic stage .”).
While Pestano teaches that serum levels are taken and measured for those being tested
for prostate cancer (see page 2 lines 1-3), Pestano does not explicitly state that the TK1 is from
serum.
Li teaches serum TK1 (STK1) is a known biomarker for prostate cancer (see abstract).
Li further teaches that STK1 concentrations are associated with Gleason scores (see page
6171).
One of ordinary skill in the art would have been motivated to combine Pestano’s
methods of predicting patient survival with serum TK1 as taught by Li, since Li teaches that
these limitations are beneficial because STK1 is known to be significantly higher in patients with
benign prostatic hyperplasia (BPH) and prostate cancer compared to healthy individuals, and
since STK1 concentration is associated with Gleason scores, it may reduce the number of
biopsies obtained from men with suspected prostate BPH/malignancy by determining STK1
concentration (see page 6178).
Regarding claim 62, Pestano teaches wherein one of the first monoclonal antibody or
first fragment thereof and the second monoclonal antibody or second fragment thereof is
immobilized to a solid support or intended to be immobilized to the solid support (see page 31 lines 16-20 “Microarrays include a solid surface (e.g., glass slide) upon which many (e.g.,
hundreds or even thousands) of specific binding agents (e.g., cDNA probes, mRNA probes, or
antibodies) are immobilized. The specific binding agents are distinctly located in an addressable
(e.g., grid) format on the array.”).
Regarding claim 65, Pestano teaches selecting a patient surveillance schedule for the
patient based on the predicted survival of the patient (see page 18 lines 9-13 “Taken in the context of the particular subject's medical history, the patient and the caregiver can make better
informed decisions of whether or not to treat (e.g., perform surgery, such as prostatectomy)
and/or whether or not to provide alternate treatment (such as, external beam radiotherapy,
brachytherapy, chemotherapy, or watchful waiting).”).
It would have been obvious to one of ordinary skill in the art at the time of the instant
application to consider combining Pestano’s methods of characterizing prostate cancer with Li’s
methods of using serum thymidine kinase 1 as a biomarker for prostate cancer. Li provides
motivation by teaching that STK1 is known to be significantly higher in patients with benign
prostatic hyperplasia (BPH) and prostate cancer compared to healthy individuals, and since
STK1 concentration is associated with Gleason scores, it may reduce the number of biopsies
obtained from men with suspected prostate BPH/malignancy by determining STK1
concentration. One of ordinary skill in the art would have been motivated to combine the
methods of Pestano and Li as they both teach prostate cancer prognostics. The artisan would
have had reasonable expectation of success based on the cumulative disclosures of these prior
art references.
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over Pestano and Li as
applied to claim 28 and in further view of Stone et al., (WO 2015/175692 A1) (IDS filed on
07/21/2022).
The teachings of Pestano and Li as it pertains to claim 28 is discussed in the 35 USC 103 rejection above. Pestano and Li do not teach estimating a hazard ration (HR) for a patient.
Regarding claim 35, Stone teaches estimating a hazard ratio (HR) for the patient based
on the determined concentration of STK protein material in the serum sample or the plasma sample, wherein predicting survival of the patient comprises predicting survival of the patient based on the estimated HR (see [0090] “Such risk may be estimated by applying the hazard ratio for a particular parameter (e.g., CCP score, Combined Score) to that parameter to yield a patient's relative risk of a particular clinical outcome (e.g., cancer recurrence or cancer-specific death). In some cases, the hazard ratio represents the relative risk increase per unit of the parameter. In some of the examples below, for instance, a single unit increase in CCP score (which represents a doubling of expression) represents a relative risk increased by the multiple of the hazard ration. Where the hazard ratio is equal to 2, for example, a single unit increase in CCP score corresponds to a doubling of relative risk (i.e., a first patient with a CCP score that is one unit higher than a second patient has twice the risk of cancer recurrence or cancer-specific death).”, see [0091] “(3) calculating said patient's risk of cancer recurrence or cancer-specific death by multiplying the number of increased units of the test value over some reference value (e.g., average values in a particular population) by the hazard ratio for the value. In some embodiments, the test value comprises the CCP score or a Combined Score as described herein and the hazard ration is any of the hazard ratios reported herein.”).
Stone teaches STK15 (see table 1 and [0055]), STK12 (see table 1), and STK17 (see
table 1), but does not explicitly teach STK1.
Li teaches serum TK1 (STK1) is a known biomarker for prostate cancer (see abstract).
One of ordinary skill in the art would have been motivated to combine Stones methods of
cancer prognosis with serum TK1 as taught by Li, since Li teaches that these limitations are
beneficial because STK1 is known to be significantly higher in patients with benign prostatic
hyperplasia (BPH) and prostate cancer compared to healthy individuals, and since STK1
concentration is associated with Gleason scores, it may reduce the number of biopsies obtained
from men with suspected prostate BPH/malignancy by determining STK1 concentration (see
page 6178). One of ordinary skill in the art would have been motivated to combine the methods
of Stone and Li as they both teach cancer prognostics. The artisan would have had reasonable
expectation of success based on the cumulative disclosures of these prior art references.
Claims 58-60 are rejected under 35 U.S.C. 103 as being unpatentable over Pestano and
Li as applied to claim 28 above, and in further view of Eriksson et al., (WO 2015094106A1) (IDS
filed on 07/21/2022).
The teachings of Pestano and Li as it pertains to claim 28 are discussed in the 35 USC
103 rejection above. Pestano and Li are silent towards SEQ ID No’s 5- 19.
Regarding claim 58, Eriksson teaches wherein the first and/or second monoclonal antibody or the first and/or second fragment thereof has a variable heavy (VH) domain complementarity determining region 1 (CDR1) having amino acid sequence SEQ ID NO: 5 (see SEQ ID NO: 6 of ‘106); a VH domain CDR2 having amino acid sequence SEQ ID NO:6 (see SEQ ID NO: 7 of ‘106); a VH domain CDR3 having amino acid sequence SEQ ID NO: 7 (see SEQ ID NO: 8 of ‘106); a variable light (VL) domain CDR1 having amino acid sequence SEQ ID NO: 8 (see SEQ ID NO: 9 of ‘106); a VL domain CDR2 having amino acid sequence SEQ ID NO: 9 (see SEQ ID NO: 10 of ‘106); and a VL domain CDR3 having amino acid sequence SEQ ID NO: 10 (see SEQ ID NO: 11 of ‘106).
One of ordinary skill in the art would have been motivated to combine Pestano and Li’s
teachings of prostate cancer prognostics with Eriksson’s teachings of antibodies capable of
binding to a serum form of human thymidine kinase 1, since Eriksson teaches these limitations
are known in the art and that the main reason for choosing an anti-TK1 antibody that is
produced against the C-terminal of TK1 is that the C-terminal region is involved in the cell cycle
regulation of TK1 (see page 1 lines 29-30).
Regarding claim 59, Eriksson teaches wherein the first and/or second monoclonal antibody or the first and/or second fragment thereof has a variable heavy (VH) domain complementarity determining region 1 (CDR1) having amino acid sequence SEQ ID NO: 5 (see SEQ ID NO: 6 of ‘106); a VH domain CDR2 having amino acid sequence SEQ ID NO: 11 (see SEQ ID NO: 12 of ‘106); a VH domain CDR3 having amino acid sequence SEQ ID NO: 12 (see SEQ ID NO: 13 of ‘106); a variable light (VL) domain CDR1 having amino acid sequence SEQ ID NO: 13 (see SEQ ID NO: 14 ‘106); a VL domain CDR2 having amino acid sequence SEQ ID NO:9 (see SEQ ID NO: 10 of ‘106); and a VL domain CDR3 having amino acid sequence SEQ ID NO: 10 (see SEQ ID NO: 11 of ‘106).
One of ordinary skill in the art would have been motivated to combine Pestano and Li’s
teachings of prostate cancer prognostics with Eriksson’s teachings of antibodies capable of
binding to a serum form of human thymidine kinase 1, since Eriksson teaches these limitations
are known in the art and that the main reason for choosing an anti-TK1 antibody that is
produced against the C-terminal of TK1 is that the C-terminal region is involved in the cell cycle
regulation of TK1 (see page 1 lines 29-30).
Regarding claim 60, Eriksson teaches wherein the first and/or second monoclonal antibody or the first and/or second fragment thereof has a variable heavy (VH) domain complementarity determining region 1 (CDR1) having amino acid sequence SEQ ID NO: 14 (see SEQ ID NO: 15 of ‘106); a VH domain CDR2 having amino acid sequence SEQ ID NO: 15 (see SEQ ID NO: 16 of ‘106); a VH domain CDR3 having amino acid sequence SEQ ID NO: 16 (see SEQ ID NO: 17 of ‘106); a variable light (VL) domain CDR1 having amino acid sequence SEQ ID NO: 17 (see SEQ ID NO: 18 of ‘106); a VL domain CDR2 having amino acid sequence SEQ ID NO: 18 (see SEQ ID NO: 19 of ‘106); and a VL domain CDR3 having amino acid sequence SEQ ID NO: 19 (see SEQ ID NO: 20 of ‘106).
One of ordinary skill in the art would have been motivated to combine Pestano and Li’s
teachings of prostate cancer prognostics with Eriksson’s teachings of antibodies capable of
binding to a serum form of human thymidine kinase 1, since Eriksson teaches these limitations
are known in the art and that the main reason for choosing an anti-TK1 antibody that is
produced against the C-terminal of TK1 is that the C-terminal region is involved in the cell cycle
regulation of TK1 (see page 1 lines 29-30).
It would have been obvious to one of ordinary skill in the art at the time of the instant
application to consider combining Pestano and Li’s methods of prostate cancer prognosis with
Eriksson’s teachings of antibodies capable of binding to a serum form of human thymidine
kinase 1. Eriksson provides motivation by teaching that the main reason for choosing an anti-TK1 antibody that is produced against the C-terminal of TK1 is that the C-terminal region is
involved in the cell cycle regulation of TK1 (see page 1 lines 29-30). Eriksson further provides
motivation by teaching that these amino acid sequences have been known in the art to be
amino acid sequences that directly bind to STK1. One of ordinary skill in the art would have
been motivated to combine the methods of Pestano and Eriksson as they both teach cancer
diagnostics and prognostics. The artisan would have had reasonable expectation of success
based on the cumulative disclosures of these prior art references.
Response to Arguments
The arguments filed on 10/24/2025 have been considered by the examiner.
On pp. 11-12 applicant argues that Pestano fails to teach (1) determining the concentration of STK1 protein material from serum or plasma sample and (2) using an ELISA kit with antibodies as defined in claim 28 determine STK1 protein concentration. Applicant argues that the body sample used in Pestano is a prostate biopsy or prostate cell samples. However, Pestano teaches that prostate cancer progression can be determined by serum levels (see page 17). Pestano further provides ranges of concentrations of serum ranging from normal to significantly elevated (see page 17). While Pestano does teach TK1 being measured in tissue samples, Pestano also teaches that serum samples may also be used to measure biomarkers. Further, Pestano explicitly teaches the use of an ELISA kit that uses antibody that specifically binds to TK1 (see page 40-41). Li explicitly teaches measuring serum STK1 (see abstract).
On pp. 12-14 applicant argues that Li does not teach any prediction of patient survival in patients diagnosed with prostate cancer. Applicant also argues that Li does not use any ELISA kit with antibodies as defined in amended claim 28 to determine the concentration of STK1 protein material in a serum or plasma sample. Li teaches that serum TK1 is a known biomarker for prostate cancer. Li teaches the biomarker STK1 being higher in individuals with prostate cancer. Pestano teaches the use of an ELISA kit with antibodies that consist of SEQ ID NO: 1, 2, 3, and 4. Pestano further teaches using the concentration of biomarkers to predict the occurrence of cancer (see page 9 discussing predicting the likelihood of a subject having a disease (e.g., prostate cancer) and predicting the reoccurrence of a disease, see page 13). Pestano teaches serum concentrations are taken and measured for those being tested for prostate cancer (see page 2).
On pp. 14-15 applicant argues that there are significant differences between Pestano, Li, and Eriksson regarding the species of TK1 that is detected or determined, because Pestano teaches TK1 in a tissue sample whereas Li and Eriksson teach STK1 in a serum sample. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Pestano teaches does teach that serum can be measured for biomarkers (see page 17). Li teaches serum TK1 being a useful biomarker for determining cancer (see abstract). Eriksson teaches measuring serum TK1 to monitor and for prognostic purpose (see page 1).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, one of ordinary skill in the art would have considered combining Pestano, Li, and Eriksson because they teach measuring TK1 in individuals to determine prognosis and diagnosis of prostate cancer. While Pestano does teach measuring TK1 in a tissue sample, Pestano also teaches measuring serum samples (see page 17). Li teaches measuring serum TK1 as a biomarker of proliferation that has been used to determine patient prognosis and treatment progress (see page 6172). Li further teaches that STK1 has become a more useful tool to assess patient prognosis, treatment progress, relapse, follow-up and survival, particularly in solid tumors (see page 6172). Eriksson teaches that measuring serum TK1 is already used in the art for monitoring and prognostics (see page 1). Eriksson further teaches that serum TK1 has sufficient sensitivity for clinical use (see page 2). It would have been obvious to one of ordinary skill in the art to substitute the tissue sample of Pestano with the serum samples taught by Li and Eriksson, as serum samples provide the benefits discussed above. The artisan would have had reasonable expectation of success based on the cumulative disclosures of these prior art references.
Conclusion
No claim is allowed.
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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/MCKENZIE A DUNN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678