DETAILED ACTION
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 .
1. The Amendment filed March 20, 2026 in response to the Office Action of December 23, 2025, is acknowledged and has been entered. Claims 90, 97, 99, 108, 147, 148, 169-174, 176-179, 181-185 are pending. Claims 90,169, 173, 174, 181 are amended. The species of IFIT3 biomarker is rejoined or examination. Claims 90, 97, 99, 108, 147, 148, 169-174, 176-179, 181-185 are currently being examined as drawn to as drawn to the elected and rejoined species of:
A. IFN, IRF4, IFNG (IFN-ɣ), TLR4, OAS1, OAS2, IFIT1, OASL, OAS3, and IFIT3;
B. lenalidomide, pomalidomide, thalidomide Compound B and Compound A; and
C. multiple myeloma and MDS.
Maintained Rejections
(addressing amendments)
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.
2. Claims 90, 97, 99, 108, 147, 148, 169-174, 176-179, 181-185 remain rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature/ a natural phenomenon) without significantly more. The claim(s) recite(s) measuring the expression level of a biomarker in a first sample from a patient before administration of therapy and measuring the expression level of the biomarker in a second sample from the patient after administration of therapy, wherein the biomarker is selected from the group consisting of DDX58, DDX60, DDX60L, GBP1, IFI27, IFI35, IFI44, IFI44L, IFIH1, IFIT1, IFIT2, IFIT3, IFITS, IFITM2, IFITM3, IRF7, ISG15, ISG20, MX1, MX2, OAS1, OAS2, OAS3, OASL, STAT, STAT3-PO4, TBK1, TBK 1-PO4, TLR7, and XAF1, wherein the therapy is Compound A or B, lenalidomide, pomalidomide, or thalidomide, and:
(i) identifying the patient as likely to be responsive to the therapy if the expression level of the biomarker in the second sample is increased compared to the first sample; or
(ii) identifying the patient as unlikely to be responsive to the therapy if the expression level of the biomarker in the second sample is NOT increased compared to the first sample; and
administering the Compound A or B, lenalidomide, pomalidomide, or thalidomide therapy to the patient identified as likely to be responsive, or
administering to the patient identified as unlikely to be responsive a treatment that does nor comprise the Compound A or B, lenalidomide, pomalidomide, or thalidomide therapy.
Claim 181 recites the same method but is limited to detecting IFNG or IRF4, wherein the therapy is Compound B, and:
(i) identifying the patient as likely to be responsive to the therapy if the expression level of IFNG in the second sample is increased compared to the first sample; or
(ii) identifying the patient as unlikely to be responsive to the therapy if the expression level of the biomarker IFNG in the second sample is NOT increased compared to the first sample; or
(iii) identifying the patient as likely to be responsive to the therapy if the expression level of IRF4 in the second sample is decreased compared to the first sample; or
(iv) identifying the patient as unlikely to be responsive to the therapy if the expression level of the biomarker IRF4 in the second sample is NOT decreased compared to the first sample; and
administering Compound B to the patient identified as likely to be responsive, or
administering to the patient identified as unlikely to be responsive a treatment that does not comprise Compound B.
Thus, the claims are directed to the judicial exception of naturally occurring increases or decreases in genes in response to therapy with Compound A or B, lenalidomide, pomalidomide, or thalidomide. This judicial exception is not integrated into a practical application because the claims recite only the detection or observation of a naturally occurring phenomenon/law of nature, which is data gathering to observe the naturally occurring phenomenon/law of nature without applying the data to a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite use of routine laboratory procedures to detect and observe naturally occurring levels of biomarkers.
The steps of measuring biomarker levels before and after therapy, are considered known, routine steps and are typically taken by those in the field to perform testing of a sample and are not elements that are sufficient to amount to significantly more than the judicial exception (see MPEP 2106.05(d)). For example, US Patent Application Publication 2015/0132313, Yao, claiming priority to 2008, discloses commercially available assay Affymetrix U133 Plus 2.0 Array used to measure the expression levels of type-I IFN and IFNα-induced pharmacodynamic marker expression profiles, by measuring levels in patient samples before, after, and during therapy to monitor changes in expression profiles indicative of disease progression and therapeutic efficacy, wherein the markers include DDX58, GBP1, IFI27, IFI35, IFI44, IFI44L, IFIH1, IFIT1, IFIT3, IFIT5, IFITM2, IFITM3, IRF7, ISG15, ISG20, MX1, MX2, OAS1, OAS2, OAS3, OASL, STAT1, STAT2, TLR7, XAF1, and IFNG ([4]; [10]; [62]; [105-109]; [139-161]; [179-182]; [320]; [463]; Example 1, 10, 11, and 13; all Tables). US Patent Application Publication 2012/0230983, Muller et al, published September 13, 2012, claiming priority to March 11, 2011, teaches monitoring cancer patient treatment response to 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (Compound A or Formula I), comprising obtaining biological samples from the cancer patient before and after administration of Compound A and measuring and comparing levels of biomarkers in the first and second samples to identify changes in biomarker levels indicative of treatment efficacy and tumor response ([49]; [55]; [104]; [112-113]; claim 42), and Muller teaches administration of Compound A can be repeated in cycling therapy, and until the patient experiences disease progression or unacceptable toxicity ([266]; [334-338]). Liu et al (Molecular Biological Reports, 2010, 37:1801-1814) teach measuring gene expression levels before and after treatment with lenalidomide, pomalidomide, and thalidomide, in tumor cell samples from subjects having cancer in order to observe expression level changes, wherein subjects were treated repeatedly daily with the therapeutic (Methods; Table 2). Giannopoulos I (Leukemia, 2009, 23:1771-1778) demonstrates detecting gene expression profiling changes in patient samples before and after therapy with thalidomide treatment and utilized commercially available HumanGenome U133 Plus2.0 Arrays (Affymetrix) to detect increases or decreases in expression levels after treatment (p. 1772, col. 2) (see prior art rejection below). Palumbo et al (Expert Opinion Drug Safety, 2012; 11:107-120) teaches lenalidomide therapy is administered repeatedly through cycles of treatment for cancer (see prior art rejection below). Infante et al (European Journal of Cancer, 2011, 47:199-205) teaches pomalidomide is administered repeatedly several days in multiple cycles to treat cancer (abstract). Giannopoulos II (Expert Opinion on Pharmacotherapy, 2011, 12:2857-2864) teaches thalidomide is repeatedly administered during the course of cancer treatment (see prior art rejection below). Routine data gathering in order to observe a natural phenomenon/ natural principle does not add a meaningful limitation to the method as it would be routinely used by those of ordinary skill in the art in order to observe the natural phenomenon/ natural principle, and it fails to narrow the scope of the claims such that others are not foreclosed from using the law of nature/natural phenomenon. Methods of detecting natural phenomenon preempt all practical uses of it as others must use/detect the natural phenomenon to apply it to any other correlations, diagnosis, prognosis, therapeutic response, monitoring, etc.
The claims now recite two possible outcomes:
(1) identifying the patient as likely to be responsive and administering Compound A or B, lenalidomide, pomalidomide, or thalidomide again; or
(2) identifying the patient as unlikely to be responsive and administering a treatment that does not comprise Compound A or B, lenalidomide, pomalidomide, or thalidomide.
With regards to outcome (1), treating patients identified as likely to be responsive to therapy, the step of administering the same therapeutic agent again after detecting an increase or decrease in the claimed biomarker expression levels fails to amount to significantly more than the judicial exception. This step is considered an insignificant extra-solution activity added to the judicial exception, because it is simply repeating the same treatment again (see MPEP 2106.05(g)).
The step of administering the same therapy again after observing changes in biomarker expression level, is also considered well-understood, routine and conventional because repeated administration of these therapies is routine and conventional during the treatment of cancer, as taught or demonstrated by Muller, Liu, Palumbo, Infante, and Giannopoulos II (see MPEP 2106.05(d)). This step can be followed by another step of gathering biomarker expression level data to observe the judicial exception again. MPEP states that mere data gathering by “i. Performing clinical tests on individuals to obtain input for an equation”, and “vi. Determining the level of a biomarker in blood” are both considered an insignificant extra-solution activity (MPEP 2106.05(g)).
MPEP 2106.05(f) states: “Another consideration when determining whether a claim integrates a judicial exception into a practical application in Step 2A Prong Two or recites significantly more than a judicial exception in Step 2B is whether the additional elements amount to more than a recitation of the words "apply it" (or an equivalent) or are more than mere instructions to implement an abstract idea or other exception on a computer. As explained by the Supreme Court, in order to make a claim directed to a judicial exception patent-eligible, the additional element or combination of elements must do "‘more than simply stat[e] the [judicial exception] while adding the words ‘apply it’". Alice Corp. v. CLS Bank, 573 U.S. 208, 221, 110 USPQ2d 1976, 1982-83 (2014) (quoting Mayo Collaborative Servs. V. Prometheus Labs., Inc., 566 U.S. 66, 72, 101 USPQ2d 1961, 1965).” MPEP 2106.05(f) states: “The Supreme Court has identified additional elements as mere instructions to apply an exception in several cases. For instance, in Mayo, the Supreme Court concluded that a step of determining thiopurine metabolite levels in patients’ blood did not amount to significantly more than the recited laws of nature, because this additional element simply instructed doctors to apply the laws by measuring the metabolites in any way the doctors (or medical laboratories) chose to use.” In the instant claims, the step of administering the same therapy again to the patient population already receiving the therapy does not amount to more than a recitation of the words "apply it" and does not meaningfully limit the claim. The claims amount to no more than administering a therapy to the patient, observing the naturally occurring changes in biomarker levels after treatment, and continuing to administer the same treatment to the same patient again.
The step of administering the same therapy again to a patient population already receiving the therapy and identified as already needing the therapy, fails to amount to significantly more than the judicial exception. MPEP 2106.05(h) states: “Another consideration when determining whether a claim integrates the judicial exception into a practical application in Step 2A Prong Two or recites significantly more than a judicial exception in Step 2B is whether the additional elements amount to more than generally linking the use of a judicial exception to a particular technological environment or field of use. As explained by the Supreme Court, a claim directed to a judicial exception cannot be made eligible "simply by having the applicant acquiesce to limiting the reach of the patent for the formula to a particular technological use." Diamond v. Diehr, 450 U.S. 175, 192 n.14, 209 USPQ 1, 10 n. 14 (1981). Thus, limitations that amount to merely indicating a field of use or technological environment in which to apply a judicial exception do not amount to significantly more than the exception itself, and cannot integrate a judicial exception into a practical application”. MPEP states: “the courts have described as merely indicating a field of use or technological environment in which to apply a judicial exception include: i. A step of administering a drug providing 6-thioguanine to patients with an immune-mediated gastrointestinal disorder, because limiting drug administration to this patient population did no more than simply refer to the relevant pre-existing audience of doctors who used thiopurine drugs to treat patients suffering from autoimmune disorders, Mayo Collaborative Servs. v. Prometheus Labs. Inc., 566 U.S. 66, 78, 101 USPQ2d 1961, 1968 (2012)”. In the instant case, the claims do no more than simply refer to the same patient population already identified as receiving the therapy to receive the therapy again.
With regards to outcome (2), treating patients identified as likely being unresponsive to therapy, the step of administering any generic “treatment” that does not comprise Compound A or B, lenalidomide, pomalidomide, or thalidomide is simply appending well-understood, routine, conventional activity of treating cancer. A treatment with “a treatment that does not comprise the compound” is a treatment specified at a high level of generality. It is a limitation that is well-understood, routine, conventional activity in the field of treating cancer and does not amount to significantly more than the judicial exception (see MPEP 2106.05(d)). The step of administering “a treatment that does not comprise the compound” is also a generic instruction to apply the judicial exception, or an insignificant extra-solution activity, and is not considered a practical application of the judicial exception. Applying or using the judicial exception to effect a particular treatment is considered a practical application, however, in the instant claims, a “treatment that does not comprise the compound” is not considered a particular treatment (see MPEP 2106.05(f)). Therefore, the judicial exception is not integrated into a practical application.
To obviate the rejection, there must be at least one additional element or physical step that applies, relies on, or uses the natural principle so that the claim amounts to significantly more than the judicial exception itself. The claimed method currently fails to provide a practical application of the judicial exception and fails to add any elements that amount to significantly more than the judicial exception.
Response to Arguments
3. Applicant argues that the claims are amended to specify "administering to the patient identified in (c) as likely to be responsive to the compound a therapeutically effective amount of the compound, or administering to the patient identified in (c) as unlikely to be responsive to the compound a treatment that does not comprise the compound". Applicant argues that the claims as amended require distinct therapeutic interventions depending on the patient's responsiveness to the compound, identified after the initial administration of the compound. Applicant argues that such distinct therapeutic interventions integrate the exception into a practical application, thus the amended independent claims 90, 169, and 181 are patent eligible under Vanda Pharm. Inc. v. West-Ward Pharm. Int Ltd., 887 F.3d 1117, 1134-1135.
4. The arguments have been considered but are not persuasive. The claims as amended now recite two outcomes:
(1) identifying the patient as likely to be responsive and administering Compound A or B, lenalidomide, pomalidomide, or thalidomide again; or
(2) identifying the patient as unlikely to be responsive and administering a treatment that does not comprise Compound A or B, lenalidomide, pomalidomide, or thalidomide.
As stated in the rejection, with regards to outcome (1), treating patients identified as likely to be responsive to therapy by administering the same therapeutic agent again after detecting the claimed increase or decrease in the claimed biomarker expression levels fails to amount to significantly more than the judicial exception. This step is considered an insignificant extra-solution activity added to the judicial exception, because it is simply repeating the same treatment again while observing biomarker changes and gathering data (see MPEP 2106.05(g)). Applicants have not persuasively argued that repeating the same treatment again while observing naturally occurring biomarker changes or collecting data amounts to significantly more than the judicial exception or practically applies the judicial exception in some way.
With regards to outcome (2), treating patients identified as likely being unresponsive to therapy, the step of administering any generic “treatment” that does not comprise Compound A or B, lenalidomide, pomalidomide, or thalidomide is simply appending well-understood, routine, conventional activity of treating cancer. A treatment with a “a treatment that does not comprise the compound” is a treatment specified at a high level of generality. It is a limitation that is well-understood, routine, conventional activity in the field of treating cancer and does not amount to significantly more than the judicial exception (see MPEP 2106.05(d)). The step of administering “a treatment that does not comprise the compound” is also a generic instruction to apply the judicial exception, or an insignificant extra-solution activity, and is not considered a practical application of the judicial exception. Applying or using the judicial exception to effect a particular treatment is considered a practical application, however, in the instant claims, a “treatment that does not comprise the compound” is not considered a particular treatment (see MPEP 2106.05(f)). Therefore, the judicial exception is not integrated into a practical application.
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.
5. NOTE: Claims 169, 173, and 174 are amended to delete the examined species of OASL and OAS3 biomarkers, therefore, Examiner has rejoined the species of IFIT3 for examination and these species are rejected below.
6. Claim(s) 169, 171, 173, 174, and 178 remain rejected under 35 U.S.C. 103 as being unpatentable over Giannopoulos I (Leukemia, 2009, 23:1771-1778) and Giannopoulos data files submitted to NCBI Gene Expression Omnibus, Series GSE15913 (published August 21, 2009: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE15913); in view of Giannopoulos II (Expert Opinion on Pharmacotherapy, 2011, 12:2857-2864).
Giannopoulos I teaches a method of monitoring thalidomide treatment response in a patient having chronic lymphocytic leukemia (CLL) cancer, including responses in the IFN-ɣ and IFN-α signaling pathways (Table 3), the method comprising:
(a) measuring the expression level of biomarkers in a first sample from the patient prior to administration of thalidomide using gene expression profiling with HumanGenome U133 Plus2.0 Arrays (Affymetrix) p. 1772, col. 2);
(b) measuring the expression level of biomarkers in a second sample from the patient after administration of thalidomide;
I detecting an increased expression of biomarkers including IFIT3 in the second sample compared to the first sample (p. 1775, col. 1-2; Figure 3; see NCBI Gene Expression Omnibus, Series GSE15913),
wherein the samples are peripheral blood mononuclear cells (same source) (p. 1772, col. 1);
wherein there was an overall response rate of 52.2% (p. 1772, col. 2, Clinical Response; Table 2).
NCBI Gene Expression Omnibus, Series GSE15913 discloses gene expression level data for 20 CLL patients before and after treatment, wherein the data tables include detection of expression for IFIT3 (Affymetrix probe ID reference 229450_at):
For example, CLL Patient #3 untreated:
Probe ID Signal Value Present (P)/Absent (A) Detection P-Value
229450_at 175.123 P 0.000244141
CLL Patient #3 thalidomide treated:
Probe ID Signal Value Present (P)/Absent (A) Detection P-Value
229450_at 310.244 P 0.000732422
Therefore, Giannopoulos demonstrates detection of increased gene expression levels of IFIT3 gene in response to thalidomide treatment.
Giannopoulos teaches administering thalidomide and assessing changes in gene expression levels for an improved understanding of in vivo effects of thalidomide, and to identify the molecular effects of thalidomide (p. 1776, col. 2; p. 1777, col. 1).
Giannopoulos I does not teach administering more of the same thalidomide to the patient after identified as having increased gene expression levels after therapy.
Giannopoulos II teaches successful clinical treatment of CLL with thalidomide (section 3), the known mechanism of action of thalidomide in CLL (Figure 1), and teaches clinical treatment regimens comprise repeated administration of thalidomide (Table 1).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer more of thalidomide to the CLL patients of Giannopoulos I. One would be motivated to, and have a reasonable expectation of success to, given: (1) Giannopoulos I and II teach thalidomide successfully treats CLL patients providing motivation and reasonable expectation of success to continue administering thalidomide, (2) Giannopoulos I teaches motivation to assess gene expression changes during treatment for an improved understanding of in vivo effects of thalidomide, and to identify the molecular effects of thalidomide; and (3) Giannopoulos II teaches known administration regimens include repeated administration of thalidomide to CLL patients for treatment, again providing motivation and reasonable expectation of success to continue repeating administration of thalidomide after testing for and observing the gene expression changes.
7. Claim(s) 169, 171-174, and 176 remain rejected under 35 U.S.C. 103 as being unpatentable over Belickova et al (Clinical Lymphoma, Myeloma, and Leukemia, October 2012, 12:375-383) and Belickova data files submitted to NCBI Gene Expression Omnibus, Series GSE31460 (published September 12, 2011: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE31460); in view of Palumbo et al (Expert Opinion Drug Safety, 2012; 11:107-120).
Belickova teaches a method of monitoring lenalidomide treatment in patients diagnosed with del(5q) myelodysplastic syndrome (MDS), the method comprising:
(a) measuring the expression level of biomarkers including IFIT3 in a first sample from the patient prior to administering lenalidomide utilizing HumanRef-8 v3 Expression BeadChips (Illumina Inc);
(b) measuring the expression level of the biomarkers in a second sample from the patient after the administration of lenalidomide and at first response to therapy (p. 376, Materials and Methods, col. 2; Figures 1-3; Table 4);
I detecting an increased expression level of the biomarkers including IFIT3 in the second sample as compared to the first sample (see Belickova published data submitted to NCBI Gene Expression Omnibus below);
wherein the first and second samples are peripheral blood samples (Materials and Methods “Samples” p. 376, col. 1).
Belickova teaches their complete raw and normalized data have been deposited in the NCBI Gene Expression Omnibus (GEO) database that is accessible through the GEO Series accession number GSE31460 (p. 378, col. 1, first paragraph).
NCBI Gene Expression Omnibus, Series GSE31460 discloses a list of samples from patients #s 1-6 of 5q- syndrome before treatment, and after treated with lenalidomide (at the time of first erythroid response). The Illumina probe name for IFIT3 is ILMN_2239754. Series GSE31460 discloses for IFIT3 expression values:
Patient #1 before treatment:
ID_REF VALUE
ILMN_2239754 17.4
Patient #1 after lenalidomide treatment at the time of first erythroid response:
ID_REF VALUE
ILMN_2239754 50.1
Patient #2 before treatment:
ID_REF VALUE
ILMN_2239754 41.5
Patient #2 after lenalidomide treatment at the time of first erythroid response:
ID_REF VALUE
ILMN_2239754 137.7
Therefore, Belickova demonstrates IFIT3 gene expression is increased in patient a sample after treatment with lenalidomide compared to baseline level prior to treatment, and expression level is increased at the time of first response to therapy. Belickova teaches lenalidomide is a thalidomide analog that was approved by the US FDA in 2005 for the treatment of patients with del(5q) MDS. Lenalidomide is an immunomodulatory drug that downregulates the production of proinflammatory cytokines TNF-α, IL-1β, and TGF-β1 by activated monocytes (p. 375, col. 2 to p. 376, col. 1).
Belickova teaches assessing changes in gene expression after treatment in order to identify genes and pathways affected by lenalidomide and to elucidate the effects of this drug (Clinical Practice Points on page 383).
Belickova does not teach administering more of the same lenalidomide to the patient identified as having increased gene expression levels at the time of first response to therapy.
Palumbo teaches lenalidomide is an immunomodulatory drug (ImiD®) oral immunomodulatory compound developed for the treatment of patients with multiple myeloma and MDS. Palumbo suggests long-term continuous treatment with lenalidomide beyond first response is important to optimize responses and delay relapse (abstract). Palumbo summarizes the known mechanisms of action and efficacy of lenalidomide in the treatment of MDS, including treatment regimens requiring repeated dosing (sections 2.2, 4.2; and 12; Table 4).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer more of the same lenalidomide to the MDS patient after detecting increased IFIT3 biomarker gene expression levels at the time of first response to therapy. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Belickova teaches lenalidomide is already known as an established, FDA approved treatment of patients with del(5q) MDS providing motivation and reasonable expectation of success to continue administering lenalidomide for treatment of patients identified as having del(5q) MDS; (2) Belickova teaches the biomarker IFIT3 is increased in gene expression after lenalidomide treatment and at the first treatment response; (3) Belickova suggests administering lenalidomide and assessing changes in gene expression levels in order to identify genes and pathways affected by lenalidomide and to elucidate the effects of this drug; (4) Palumbo also teaches lenalidomide is a known, established, successful therapeutic for the treatment of del(5q) MDS that is administered in repeated doses; and (5) Palumbo suggests long-term continuous treatment with lenalidomide beyond first response is important to optimize responses and delay relapse, thereby providing both motivation and reasonable expectation of success to continue administering lenalidomide after testing for and observing gene expression changes for continued treatment.
8. Claim(s) 178 remains rejected under 35 U.S.C. 103 as being unpatentable Belickova et al (Clinical Lymphoma, Myeloma, and Leukemia, October 2012, 12:375-383) and Belickova data files submitted to NCBI Gene Expression Omnibus, Series GSE31460 (published September 12, 2011: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE31460) and of Palumbo et al (Expert Opinion Drug Safety, 2012; 11:107-120); as applied to claims 169, 171-174, and 176 above, and further in view of Bouscary et al (British Journal of Hematology; 2005, 131:609-618), and Giannopoulos I (Leukemia, 2009, 23:1771-1778) and Giannopoulos I data files submitted to NCBI Gene Expression Omnibus, Series GSE15913 (published August 21, 2009: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE15913).
Belickova, their published data at NCBI Gene Expression Omnibus, Series GSE31460, and Palumbo (the combined references) teach a method of monitoring lenalidomide treatment in patients diagnosed with del(5q) myelodysplastic syndrome (MDS), the method comprising:
(a) measuring the expression level of biomarkers including IFIT3 in a first sample from the patient prior to administering lenalidomide;
(b) measuring the expression level of the biomarkers in a second sample from the patient after the administration of lenalidomide and at first response to therapy;
I detecting an increased expression level of the biomarkers including IFIT3 in the second sample as compared to the first sample; and
(d) administering to the patient a therapeutically effective amount of lenalidomide, as set forth above.
As stated above, Belickova teaches lenalidomide is an ImiD that is a thalidomide analog. Palumbo also teaches lenalidomide is a thalidomide analog (section 6). Belickova teaches measuring changes in gene expression levels to identify signaling pathways that are affected by lenalidomide and to help explain the effects of the drug (abstract; Clinical Practice Points on p. 383).
The combined references do not teach administering thalidomide.
Bouscary teaches treating MDS patients, including 5q deletions, with thalidomide and repeated administration, wherein patients responded to therapy (abstract; p. 612, col. 2). Bouscary teaches other known studies treating MDS with thalidomide (Table VI). Bouscary teaches the need to identify patients who will respond to therapy (p. 616-617, Discussion), and assesses the effects of lenalidomide on signaling pathways related to bone marrow apoptosis and angiogenesis, in order to help identify mechanisms of thalidomide in MDS (p. 610, col. 1; Table V).
Giannopoulos I teaches applying gene expression profiling to leukemic cancer patient samples taken before and after treatment with thalidomide in order to identify changes in signaling pathways that are affected by thalidomide and to better understand the molecular basis of clinical response to thalidomide (p. 1772, col. 2). Giannopoulos conducted gene expression profiling with Affymetrix HumanGenome U133 Plus2.0 Arrays, and deposited the data at Gene Expression Omnibus, Series GSE15913 (p. 1771, col. 2; p. 1775, col. 1-2). NCBI Gene Expression Omnibus, Series GSE15913 discloses gene expression data for 20 CLL patients before and after thalidomide treatment, wherein patients demonstrated increased expression of IFIT3 after treatment with thalidomide (see rejection above).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute thalidomide for its analog lenalidomide in the method of the combined references. One would have been motivated to, and have a reasonable expectation of success to because: (1) thalidomide is a functional equivalent of its analog lenalidomide and both are administered for the successful treatment of MDS and other hematological malignancies, providing a reasonable expectation of success to achieve the same result; and (2) Belickova, Bouscary, and Giannopoulos I teach the need to determine signaling pathways and gene expression profiles affected by thalidomide or lenalidomide treatment in order to help identify mechanisms of their action, wherein commercially available assays were successfully used to measure gene expression levels of biomarkers including IFIT3 in patient samples before and after treatment.
9. Claim(s) 170 remains rejected under 35 U.S.C. 103 as being unpatentable Belickova et al (Clinical Lymphoma, Myeloma, and Leukemia, October 2012, 12:375-383) and Belickova data files submitted to NCBI Gene Expression Omnibus, Series GSE31460 (published September 12, 2011: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE31460), Palumbo et al (Expert Opinion Drug Safety, 2012; 11:107-120); Bouscary et al (British Journal of Hematology; 2005, 131:609-618), Giannopoulos I (Leukemia, 2009, 23:1771-1778) and Giannopoulos I data files submitted to NCBI Gene Expression Omnibus, Series GSE15913 (published August 21, 2009: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE15913); as applied to claims 169, 171-174, 176, and 178 above, and further in view of Raza et al (Cancer, 2008, 113:1596-1604).
Belickova, Belickova published data at NCBI Gene Expression Omnibus, Series GSE31460, Palumbo, Bouscary, Giannopoulos I, and Giannopoulos I data files submitted to NCBI Gene Expression Omnibus, Series GSE15913 (the combined references) teach a method of monitoring thalidomide treatment in patients diagnosed with del(5q) myelodysplastic syndrome (MDS), the method comprising:
(a) measuring the expression level of biomarkers including IFIT3 in a first sample from the patient prior to administering thalidomide;
(b) measuring the expression level of the biomarkers in a second sample from the patient after the administration of thalidomide and at first response to therapy;
I detecting an increased expression level of the biomarkers including IFIT3 in the second sample as compared to the first sample; and
(d) administering to the patient a therapeutically effective amount of thalidomide, wherein the samples tested are peripheral blood with monocytes isolated (see p. 376, col. 1 of Belickova).
The combined references do not teach the samples are bone marrow biopsies.
Raza teaches assaying gene expression profiles in mononuclear cells of bone marrow biopsies from MDS patients before and after patient treatment with thalidomide (“Samples” and “Oligonucleotide microarrays” p. 1597, col. 2 to p. 1598, col. 1). Raza teaches MDS is a complex and heterogeneous disease in which the bone marrow microenvironment plays an important role in perpetuating the malignant clone. Thalidomide mainly targets the components of the bone marrow microenvironment (p. 1601, col. 1 to p. 1603, col. 1). Raza teaches determining gene expression profiles to distinguish patients who respond to therapy from those who do not (p. 1603, col. 1-2; Figure 2).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to assay samples from bone marrow biopsies in the method of the combined references. One would have been motivated to, and have a reasonable expectation of success to because: (1) the combined references teach assaying gene expression profiles in response to thalidomide therapy to better understand the effects and clinical response to thalidomide; (2) Raza teaches determining gene expression profiles to distinguish clinical response to thalidomide and that thalidomide targets the bone marrow; and (3) the combined references tested gene expression profiles of MDS patients in mononuclear cells from peripheral blood samples and Raza demonstrates successfully testing gene expression profiles of MDS patients in mononuclear cells from bone marrow biopsies. Given all of the cited art teach the need to profile gene expression in patient samples in response to thalidomide treatment, and the cited art teach successfully utilizing mononuclear cells from either peripheral blood or bone marrow biopsy for gene expression profiling, one of skill in the art would have a reasonable expectation of success to utilize bone marrow biopsies in the method of the combined references as the sample to assay for gene expression profiling in response to therapy.
10. Claim(s) 177 remains rejected under 35 U.S.C. 103 as being unpatentable over Belickova et al (Clinical Lymphoma, Myeloma, and Leukemia, October 2012, 12:375-383) and Belickova data files submitted to NCBI Gene Expression Omnibus, Series GSE31460 (published September 12, 2011: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE31460); Palumbo et al (Expert Opinion Drug Safety, 2012; 11:107-120); Bouscary et al (British Journal of Hematology; 2005, 131:609-618), and Giannopoulos I (Leukemia, 2009, 23:1771-1778); as applied to claims 169, 171-174,176, and 178 above, and further in view of Zhu et al (Leukemia Lymphoma, April 2013, 54:683-687).
Belickova and their published data at NCBI Gene Expression Omnibus, Series GSE31460, Palumbo, Bouscary, and Giannopoulos I (the combined references) teach a method of monitoring lenalidomide or thalidomide treatment in patients diagnosed with del(5q) myelodysplastic syndrome (MDS), the method comprising:
(a) measuring the expression level of biomarkers including IFIT3 in a first sample from the patient prior to administering lenalidomide or thalidomide;
(b) measuring the expression level of the biomarkers in a second sample from the patient after the administration of lenalidomide or thalidomide and at first response to therapy;
I detecting an increased expression level of the biomarkers including IFIT3 in the second sample as compared to the first sample; and
(d) administering to the patient a therapeutically effective amount of lenalidomide or thalidomide, as set forth above.
The combined references do not teach administering pomalidomide.
Zhu summarizes the functional equivalence of ImiDs thalidomide and its analogs lenalidomide and pomalidomide in their molecular effects and the treatment of hematological cancers (p. 2-3).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute pomalidomide for thalidomide or lenalidomide in the method of the combined references. One would have been motivated to, and have a reasonable expectation of success to because: (1) lenalidomide and thalidomide are demonstrated to treat MDS; (2) pomalidomide is a known ImiD functional equivalent of thalidomide and pomalidomide used for the treatment of hematological malignancies; (3) lenalidomide demonstrated success treating MSD and increasing IFIT3 gene expression, providing a reasonable expectation of success for its functional equivalent pomalidomide to perform the same; and (4) Belickova and Giannopoulos I teach the need to assess changes in gene expression levels during ImiD treatment to identify the pathways they affect and their molecular mechanisms.
Response to Arguments
11. Applicants argue that Giannopoulos I and Belickova teach a method comprising detecting increased expression of biomarkers including OASL and OAS3, however the claims have been amended to delete OASL and OAS3.
12. The arguments have been considered but are not persuasive. Given Applicants deleted the examined species of OASL and OAS3, the species of IFIT3 was rejoined for examination. Giannopoulos I and Belickova teach a method comprising detecting increased expression of biomarkers including IFIT3, as set forth above.
13. Conclusion: No claim is allowed.
Conclusion
14. 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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/Laura B Goddard/Primary Examiner, Art Unit 1642
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