DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This action is responsive to the Response to Restriction Requirement filed 18 January 2026, in which claims 42-46 and 58 were amended. Claims 43-47 are now withdrawn (see paragraphs 3-5 below), and claims 41-42 and 48-61 are under consideration herein. It is reiterated that claims 41-61 were newly added with the RCE filed 08 October 2025; in view of the cancelation of all previously pending claims (claims 18-20, 23-27, 30-33, and 35-40), all prior rejections of those claims are now moot. Claims 41-42 and 48-61 are now rejected for the reasons given below. This action is non-final.
Election/Restriction
Applicant’s prior election of Group III, and of the species of KRAS, in the reply filed on April 3, 2023 is again acknowledged.
Applicant’s new election of “Species c”, methods requiring NFKBIA as the group B gene, in the reply filed on 18 January 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claims 41-42 and 48-61 are under consideration herein as directed to the elected species, which includes the previously elected gene KRAS (now recited in both independent claims as a “group A” gene), and the newly elected gene NFKBIA (recited in both independent claims as a “group B” gene). It is noted that claim 58 is under consideration as directed to KRAS and NFKBIA (i.e., the “optional” additional genes recited in the claim have not been considered as the prior art applies against the claims as directed to KRAS and NFKBIA).
Claims 43-47 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 18 January 2026.
Claim Interpretation
Regarding all claims (and particularly see the language of new independent claims 41 and 57), it is noted that the terms “first treatment” and “second treatment” are not employed in the application as filed (although the specification does refer to an “initial treatment”, and thus discloses the concept of an initial or first type of treatment for a subject [see, e.g., paragraph 73 of the published application]). As used in the present claims, the language “administering a first treatment” followed by “administering a second treatment” is analogous to the disclosure in the application of methods in which “administering treatment” is followed by “modifying treatment” in cases when “the treatment” is not effective (see, e.g., original claim 18 and the discussion at paragraph 12 of the published application). Thus, the recitations of “first treatment” and “second treatment’ in the claims are interpreted as referencing the relative timing of two different treatments (i.e., a “first treatment” occurring prior to a “second treatment”), rather than a requirement for a “first treatment” that is the initial/first type of treatment administered to a treatment naïve subject (and a “second treatment” that is literally the “second” type of treatment provided to a subject).
Claim Objections
Claim 48 is objected to because of the following informalities: the claim recites “wherein the somatic aberrations comprises” rather than “wherein the somatic aberrations comprise”. While it is noted that the reference to “the somatic aberrations” is interpreted as collectively referencing all tested/detected aberrations, correction of the grammatical error is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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) 41-42, 48-53, and 55-61 are rejected under 35 U.S.C. 103 as being unpatentable over Spencer et al (US 2018/0282820 A1 [4 Oct 2018]; previously cited) in view of Weaver et al (Seminars in Oncology Nursing 33(3):237-253 [Aug 2017]; cited herein) and Bolli et al (including Supplementary Information) (Nature Communications 5:2997 [Jan 2014]; cited herein).
Spencer et al disclose methods for monitoring multiple myeloma (MM) treatment response, which methods may comprise obtaining cell-free nucleic acids from a sample of peripheral blood of an individual who has undergone treatment for MM, and testing the cell-free nucleic acids for mutations in genes including KRAS (corresponding to Applicant’s “group A” elected gene) (see the entire reference, including the Abstract). Among embodiments of their invention taught by Spencer et al are methods in which cell-free nucleic acids from an individual who has undergone treatment for MM are tested for KRAS and other mutations to “form a test sample profile”, which profile is compared to a pre-treatment control profile of the subject, and which control profile contains data regarding the individual’s status with regard to the same mutations prior to treatment (see, e.g., paragraphs 52-62, as well as claims 1-6). With regard to such a ”control profile”, Spencer et al teach that this is derived from the same type of sample from the same subject at an earlier timepoint, and may provide “a baseline or basal level profile” of information regarding presence or absence of mutations (see, e.g., paragraphs 184-186); Spencer et al thus disclose performing with regard to the KRAS gene methods including steps i)-iii) of independent claims 41 and 57, with the treatment referenced by Spencer et al being equivalent to the “first treatment” of the instant claims. It is noted that Spencer et al teach performing mutation detection via whole exome sequencing (see, e.g., paragraph 174) and various types of “next generation” sequencing (see, e.g., paragraph 217). Spencer et al also disclose that “an absence of, or reduction in the number of, mutations in a nucleotide sequence from a KRAS….gene indicates a response of the individual to treatment for multiple myeloma” (see, e.g., the Abstract and paragraphs 55 and 59), and also teach methods including steps in which a subject may be determined to have not responded to a treatment when “the number of mutations…..in the test sample profile is the same or higher than the control profile” (see again, e.g., paragraph 55 and claims 1-2).
Spencer et al then teach that any of their disclosed embodiments (which include the method above) may further comprise “the step of administering one or more drugs to treat the individual”, which treatment preferably “includes administering a drug or drugs which is/are different to that previously administered to the patient, such that the overall treatment of the individual for multiple myeloma is modified” (see paragraphs 63-72). Of particular relevance to the “administering” of independent claims 41 and 57, Spencer et al specifically teach employing drugs to target specific detected mutations, and also disclose “the step of determining to cease administration of a particular drug and commence an alternative treatment where it is determined that the mutations of the individual are not responsive to the current treatment protocol”, as well as a “step of determining to maintain administration of a drug which targets a specific mutation, and supplementing the treatment protocol by the addition of one or more drugs which target different mutations in the individual” (see paragraphs 72-73, and also see claims 26-27).
Spencer et al thus also disclose a type of further “administering” meeting the requirements of iv) of independent claims 41 and 57 in relation to mutations detected in the KRAS gene, with the “alternative” treatment provided following cessation of the original treatment meeting the requirements of a “second” treatment as set forth in the claims. However, while it is reiterated that Spencer et al teach both an absence of, or reduction in the number of, mutations may function as an indicator of treatment response, while mutation levels that are “the same or higher” may indicate non-response (and thus a need for a different treatment)(see again, e.g., paragraph 55),
Spencer et al are silent with regard to performing detection of somatic aberrations in the elected “group B” gene NFKBIA in such subjects with multiple myeloma, and thus fail to teach methods meeting all of the requirements of the elected species.
Weaver et al provide a “systematic review” of multiple myeloma (MM) genomics, teaching that “genetic changes play a role in the pathogenesis of MM, prognostication, and therapeutic targets for novel therapies” (see entire reference, particularly the Abstract). Weaver et al teach that KRAS is among the most commonly mutated genes in MM (see the Abstract, Tables 1-2, and page 248, right column, second full paragraph), and also teach that NFKBIA has been disclosed as exhibiting genetic changes in MM (see Table 1 at page 245, citing to Bolli et al). Weaver et al also teach that mutations detected in MM are known to be relevant to therapy selection and development of “targeted novel therapies”, and that next generation sequencing “can be used to identify genomic alterations associated with the acquisition of drug resistance and to facilitate improvements in the overall treatment of MM” (see page 249, “Treatment of MM”).
Turning to the Bolli et al reference, Bolli et al also teach the association of KRAS mutations with MM; see, e.g., the discussion of KRAS as being among “recurrent mutated genes of likely pathogenic significance” in MM at page 2, left column, first full paragraph, as a “known driver mutation” that they identified in patients (see page 3, both columns; Figures 2-3, and page 6, left column). Bolli et al also report the identification of “new clonal mutations” in a patient with ascites relapse, with the group of three genes exhibiting such mutations including NFKBIA (see page 6, left column, third full paragraph, and see also Supplementary Figure S2). Bolli et al thus disclose that they identified a clonal somatic aberration in the NFKBIA gene in a relapsed MM patient, which identification was achieved via serial sampling as taught by Bolli et al (see entire reference, particularly page 3, right column under the heading “Clonal evolution” bridging to page 6, left column). (It is noted that this teaching of Bolli et al also establishes that the type of genetic change in NFKBIA disclosed by Weaver et al meets the claim limitation of being a “somatic aberration”.) As Bolli et al disclose performing whole exome sequencing on their samples (including their serial samples), Bolli et al also inherently teach detection of somatic aberrations in each of their sequenced genes (which include both KRAS and NFKBIA) at multiple timepoints, resulting in evaluation of changes in mutation/genomic aberration status over time (see the Abstract; page 2, left column, second full paragraph; page 10, right column “Methods” bridging to page 11; and Supplemental Figure S2). Similar to Weaver et al, Bolli et al also teach that the types of mutations detected in samples from MM patients (as well as whether those mutations are clonal or subclonal) have therapeutic implications (see page 10, both columns), and Bolli et al further teach that the “presence of high variability in genomic architecture across samples highlights the need for therapeutic interventions directed at multiple targets rather than a single genomic anomaly, and underscores the striking success of combination therapies”, further noting that there is a movement “towards an era of personalized therapy for myeloma” (page 10, right column).
In view of the teachings of Weaver et al and Bolli et al, it would have been prima facie obvious before the effective filing date of the claimed invention to have modified the methods of Spencer et al so as to have included therein the detection of any somatic aberrations in the NFKBIA gene, and to have considered an increase in mutations in NFKBIA (along with changes in KRAS mutation status) as an indicator of a need to modify patient therapy to a “second”/different therapy (and conversely, to have interpreted loss of mutations in either or both genes as an indicator of therapy effectiveness and thus as a motivation to continue the same “first” therapy); the combined teachings of Spencer et al, Weaver et al, and Bolli et al thus suggest methods meeting all requirements of the claims, including an “administering” meeting the requirements of step iv). All of Spencer et al, Weaver et al, and Bolli et al teach the significance of the KRAS gene and its role as a therapy target in MM, while both Weaver et al and Bolli et al suggest the benefit of also testing and considering NFKBIA mutation status in therapy selection (with Bolli et al further establishing that NFKBIA has been demonstrating as exhibiting a clonal somatic aberration in at least one testing MM relapse sample). An ordinary artisan would have been motivated to have made such a modification for the benefit of more successfully provided a “personalized” therapy for a MM patient based on the actual mutation patterns exhibited in serial tested samples, and – given the detailed guidance provided by Spencer et al and Bolli et al with regard to sample testing – would have had a reasonable expectation of success in performing such methods.
With further regard to dependent claims 42 and 58, the NFKBIA gene is addressed in detail above (and with further regard to claim 58, it is noted that the additional genes recited in that claim are only “optionally” included; as the prior art applies against the claims as directed to the elected species, search and examination was not extended to additional gene combinations).
Regarding dependent claim 48, the teachings of Spencer et al, Weaver et al, and Bolli et al (as are discussed above) would have suggested the detection of any and all types of somatic aberrations in KRAS and NFKBIA (as well as any other genes disclosed as being associated with MM), for the benefit of fully characterizing the mutation profile of a patient undergoing treatment; further, the performance of whole exome sequencing (as taught by the cited art) would have necessarily achieved detection of somatic aberrations of the types set forth in the claim.
Regarding dependent claim 49, the alternatives of whole exome sequencing (WES) (as well as next generation sequencing (NGS)) have been addressed above.
Regarding claims 50-52 and 59-61, Spencer et al teach the testing of cfDNA from blood, as well as the testing of circulating tumor cells/nucleic acids from such circulating cells (see, e.g., paragraphs 174-178); it is noted that Weaver et al also teach the relevance of circulating tumor cells in peripheral blood as diagnostic targets (see Table 1).
With further regard to dependent claims 53 and 55, the types of therapies disclosed by Spencer et al as being employed in further treatment of MM patients include stem cell transplant and chemotherapy, including several of the preferred chemotherapies of claim 55 (dexamethasone, lenalidomide, etc., see paragraphs 63-64), such that these specific types of therapies are suggested by the combined teachings of Spencer et al, Weaver et al, and Bolli et al.
Regarding dependent claim 56, the cited art clearly discloses and provides motivation for the performance of the testing of serial samples and the adjustment of therapy based on testing results, as discussed above; accordingly, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have continued to perform such further testing and adjustment of therapy repeatedly/throughout treatment of a patient, simply for the benefit of more appropriately and successfully treating that patient.
Accordingly, all of claims 41-42, 48-53, and 55-61 are prima facie obvious over the teachings of Spencer et al in view of Weaver et al and Bolli et al.
Claim(s) 54 is rejected under 35 U.S.C. 103 as being unpatentable over Spencer et al, Weaver et al, and Bolli et al, as applied to claims 41-42, 58-43, and 55-61, above, and further in view of Chen et al (British Journal of Haematology 162:483-488 [2013]; cited herein).
The relevant teachings of Spencer et al, Weaver et al, and Bolli et al are set forth above. While the combined teachings of Spencer et al, Weaver et al, and Bolli et al include the use of chemotherapy and other therapy types in the treatment of MM, as well as the modification of such therapies in response to detection of somatic aberrations /mutational profiles (as discussed above), none of Spencer et al, Weaver et al, and Bolli et al explicitly disclose treatment of MM via administration of both chemotherapy and radiation as required by claim 54 (although it is reiterated that Spencer et al in view of Weaver et al and Bolli et al generally teach and provide motivation to detect somatic aberrations prior to and after any type of MM therapy, for the reasons/benefits already discussed).
Chen et al disclose that MM may spread to the central nervous system (CNS), teaching that such disease extension – which may be present at diagnosis or at relapse - generally has a “dismal prognosis” (see entire reference, particularly page 483). Chen et al report that long term survival of such MM CNS was achieved via the use of a combination of radiation, chemotherapy, and immunomodulatory agents, a “triple modality approach” (see again the entire reference, particularly page 483, as well as page 487, bottom of right column bridging to page 488, top of left column).
In view of the teachings of Chen et al, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the methods suggested by Spencer et al, Weaver et al, and Bolli et al so as to have employed the triple therapy taught by Chen et al, including the use of radiation and chemotherapy, in the treatment of MM patients of the type taught by Chen et al, and thereby to have performed methods meeting the requirements of claim 54. An ordinary artisan would have been motivated to have made such a modification for the advantage of improving the survival of such a patient, as taught by Chen et al. It is further noted that an ordinary artisan would have been motivated to have performed such a treatment at whatever point such disease was first diagnosed, including as a first treatment prior to further testing/detection of somatic aberrations (and Chen et al make clear that such disease may be present either at initial diagnosis or relapse). Further, given Chen et al’s reported data, an ordinary artisan would have had a reasonable expectation of success in performing such methods.
Claim(s) 41-42, 48-53, and 55-61 are rejected under 35 U.S.C. 103 as being unpatentable over Spencer et al-2 (WO 2017/091865 A1 [8 June 2017]; previously cited) in view of Weaver et al (Seminars in Oncology Nursing 33(3):237-253 [Aug 2017]; cited herein) and Bolli et al (including Supplementary Information) (Nature Communications 5:2997 [Jan 2014]; cited herein).
Spencer et al-2 disclose methods for monitoring multiple myeloma (MM) treatment response, which methods may comprise obtaining cell-free nucleic acids from a sample of peripheral blood of an individual who has undergone treatment for MM, and testing the cell-free nucleic acids for mutations in genes including KRAS (corresponding to Applicant’s “group A” elected gene) (see the entire reference, including the Abstract). Among embodiments of their invention taught by Spencer et al-2 are methods in which cell-free nucleic acids from an individual who has undergone treatment for MM are tested for KRAS and other mutations to “form a test sample profile”, which profile is compared to a pre-treatment control profile of the subject, and which control profile contains data regarding the individual’s status with regard to the same mutations prior to treatment (see, e.g., page 6, line 7-page 8, line 2, as well as claims 1-6). With regard to such a ”control profile”, Spencer et al-2 teach that this is derived from the same type of sample from the same subject at an earlier timepoint, and may provide “a baseline or basal level profile” of information regarding presence or absence of mutations (see page 24, line 25-page 25, line 11); Spencer et al-2 thus disclose performing with regard to the KRAS gene methods including steps i)-iii) of independent claims 41 and 57, with the treatment referenced by Spencer et al-2 being equivalent to the “first treatment” of the instant claims. . It is noted that Spencer et al teach performing mutation detection via whole exome sequencing (see, e.g., page 22, line 19-page 23, line 4) and various types of “next generation” sequencing (see, e.g., page 31, line 27-page 32, line 20). Spencer et al-2 also disclose that “an absence of, or reduction in the number of, mutations in a nucleotide sequence from a KRAS….gene indicates a response of the individual to treatment for multiple myeloma” (see, e.g., the Abstract; page 6, lines 16-19; page 7, lines 4-6 and 18-20; claims 1-2), and also teach methods including steps in which a subject may be determined to have not responded to a treatment when “the number of mutations…..in the test sample profile is the same or higher than the control profile” (see again, e.g., page 7, lines 6-10, and claims 1-2).
Spencer et al-2 then teach that any of their disclosed embodiments (which include the method above) may further comprise “the step of administering one or more drugs to treat the individual”, which treatment preferably “includes administering a drug or drugs which is/are different to that previously administered to the patient, such that the overall treatment of the individual for multiple myeloma is modified” (see page 8, line 3-page 9, line 21). Of particular relevance to the “administering” of independent claims 41 and 57, Spencer et al-2 specifically teach employing drugs to target specific detected mutations, and also disclose “the step of determining to cease administration of a particular drug and commence an alternative treatment where it is determined that the mutations of the individual are not responsive to the current treatment protocol”, as well as a “step of determining to maintain administration of a drug which targets a specific mutation, and supplementing the treatment protocol by the addition of one or more drugs which target different mutations in the individual” (see page 9, lines 12-21, and also see claims 26-27).
Spencer et al-2 thus also disclose a type of further “administering” meeting the requirements of iv) of independent claims 41 and 57 in relation to mutations detected in the KRAS gene, with the “alternative” treatment provided following cessation of the original treatment meeting the requirements of a “second” treatment as set forth in the claims. However, while it is reiterated that Spencer et al-2 teach both an absence of, or reduction in the number of, mutations may function as an indicator of treatment response, while mutation levels that are “the same or higher” may indicate non-response (and thus a need for a different treatment)(see again, e.g., page 7, lines 4-10),
Spencer et al-2 are silent with regard to performing detection of somatic aberrations in the elected “group B” gene NFKBIA in such subjects with multiple myeloma, and thus fail to teach methods meeting all of the requirements of the elected species.
Weaver et al provide a “systematic review” of multiple myeloma (MM) genomics, teaching that “genetic changes play a role in the pathogenesis of MM, prognostication, and therapeutic targets for novel therapies” (see entire reference, particularly the Abstract). Weaver et al teach that KRAS is among the most commonly mutated genes in MM (see the Abstract, Tables 1-2, and page 248, right column, second full paragraph), and also teach that NFKBIA has been disclosed as exhibiting genetic changes in MM (see Table 1 at page 245, citing to Bolli et al). Weaver et al also teach that mutations detected in MM are known to be relevant to therapy selection and development of “targeted novel therapies”, and that next generation sequencing “can be used to identify genomic alterations associated with the acquisition of drug resistance and to facilitate improvements in the overall treatment of MM” (see page 249, “Treatment of MM”).
Turning to the Bolli et al reference, Bolli et al also teach the association of KRAS mutations with MM; see, e.g., the discussion of KRAS as being among “recurrent mutated genes of likely pathogenic significance” in MM at page 2, left column, first full paragraph, as a “known driver mutation” that they identified in patients (see page 3, both columns; Figures 2-3, and page 6, left column). Bolli et al also report the identification of “new clonal mutations” in a patient with ascites relapse, with the group of three genes exhibiting such mutations including NFKBIA (see page 6, left column, third full paragraph, and see also Supplementary Figure S2). Bolli et al thus disclose that they identified a clonal somatic aberration in the NFKBIA gene in a relapsed MM patient, which identification was achieved via serial sampling as taught by Bolli et al (see entire reference, particularly page 3, right column under the heading “Clonal evolution” bridging to page 6, left column). (It is noted that this teaching of Bolli et al also establishes that the type of genetic change in NFKBIA disclosed by Weaver et al meets the claim limitation of being a “somatic aberration”.) As Bolli et al disclose performing whole exome sequencing on their samples (including their serial samples), Bolli et al also inherently teach detection of somatic aberrations in each of their sequenced genes (which include both KRAS and NFKBIA) at multiple timepoints, resulting in evaluation of changes in mutation/genomic aberration status over time (see the Abstract; page 2, left column, second full paragraph; page 10, right column “Methods” bridging to page 11; and Supplemental Figure S2). Similar to Weaver et al, Bolli et al also teach that the types of mutations detected in samples from MM patients (as well as whether those mutations are clonal or subclonal) have therapeutic implications (see page 10, both columns), and Bolli et al further teach that the “presence of high variability in genomic architecture across samples highlights the need for therapeutic interventions directed at multiple targets rather than a single genomic anomaly, and underscores the striking success of combination therapies”, further noting that there is a movement “towards an era of personalized therapy for myeloma” (page 10, right column).
In view of the teachings of Weaver et al and Bolli et al, it would have been prima facie obvious before the effective filing date of the claimed invention to have modified the methods of Spencer et al-2 so as to have included therein the detection of any somatic aberrations in the NFKBIA gene, and to have considered an increase in mutations in NFKBIA (along with changes in KRAS mutation status) as an indicator of a need to modify patient therapy to a “second”/different therapy (and conversely, to have interpreted loss of mutations in either or both genes as an indicator of therapy effectiveness and thus as a motivation to continue the same “first” therapy); the combined teachings of Spencer et al-2, Weaver et al, and Bolli et al thus suggest methods meeting all requirements of the claims, including an “administering” meeting the requirements of step iv). All of Spencer et al-2, Weaver et al, and Bolli et al teach the significance of the KRAS gene and its role as a therapy target in MM, while both Weaver et al and Bolli et al suggest the benefit of also testing and considering NFKBIA mutation status in therapy selection (with Bolli et al further establishing that NFKBIA has been demonstrating as exhibiting a clonal somatic aberration in at least one testing MM relapse sample). An ordinary artisan would have been motivated to have made such a modification for the benefit of more successfully provided a “personalized” therapy for a MM patient based on the actual mutation patterns exhibited in serial tested samples, and – given the detailed guidance provided by Spencer et al-2 and Bolli et al with regard to sample testing – would have had a reasonable expectation of success in performing such methods.
With further regard to dependent claims 42 and 58, the NFKBIA gene is addressed in detail above (and with further regard to claim 58, it is noted that the additional genes recited in that claim are only “optionally” included; as the prior art applies against the claims as directed to the elected species, search and examination was not extended to additional gene combinations).
Regarding dependent claim 48, the teachings of Spencer et al-2, Weaver et al, and Bolli et al (as are discussed above) would have suggested the detection of any and all types of somatic aberrations in KRAS and NFKBIA (as well as any other genes disclosed as being associated with MM), for the benefit of fully characterizing the mutation profile of a patient undergoing treatment; further, the performance of whole exome sequencing (as taught by the cited art) would have necessarily achieved detection of somatic aberrations of the types set forth in the claim.
Regarding dependent claim 49, the alternatives of whole exome sequencing (WES) (as well as next generation sequencing (NGS)) have been addressed above.
Regarding claims 50-52 and 59-61, Spencer et al-2 teach the testing of cfDNA from blood, as well as the testing of circulating tumor cells/nucleic acids from such circulating cells (see, e.g., page 22, line 19-page 23, line 25); it is noted that Weaver et al also teach the relevance of circulating tumor cells in peripheral blood as diagnostic targets (see Table 1).
With further regard to dependent claims 53 and 55, the types of therapies disclosed by Spencer et al-2 as being employed in further treatment of MM patients include stem cell transplant and chemotherapy, including several of the preferred chemotherapies of claim 55 (dexamethasone, lenalidomide, etc., see page 8, lines 3-21), such that these specific types of therapies are suggested by the combined teachings of Spencer et al, Weaver et al, and Bolli et al.
Regarding dependent claim 56, the cited art clearly discloses and provides motivation for the performance of the testing of serial samples and the adjustment of therapy based on testing results, as discussed above; accordingly, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have continued to perform such further testing and adjustment of therapy repeatedly/throughout treatment of a patient, simply for the benefit of more appropriately and successfully treating that patient.
Accordingly, all of claims 41-42, 48-53, and 55-61 are prima facie obvious over the teachings of Spencer et al-2 in view of Weaver et al and Bolli et al.
Claim(s) 54 is rejected under 35 U.S.C. 103 as being unpatentable over Spencer et al-2, Weaver et al, and Bolli et al, as applied to claims 41-42, 58-43, and 55-61, above, and further in view of Chen et al (British Journal of Haematology 162:483-488 [2013]; cited herein).
The relevant teachings of Spencer et al-2, Weaver et al, and Bolli et al are set forth above. While the combined teachings of Spencer et al-2, Weaver et al, and Bolli et al include the use of chemotherapy and other therapy types in the treatment of MM, as well as the modification of such therapies in response to detection of somatic aberrations /mutational profiles (as discussed above), none of Spencer et al-2, Weaver et al, and Bolli et al explicitly disclose treatment of MM via administration of both chemotherapy and radiation as required by claim 54 (although it is reiterated that Spencer et al-2 in view of Weaver et al and Bolli et al generally teach and provide motivation to detect somatic aberrations prior to and after any type of MM therapy, for the reasons/benefits already discussed).
Chen et al disclose that MM may spread to the central nervous system (CNS), teaching that such disease extension – which may be present at diagnosis or at relapse - generally has a “dismal prognosis” (see entire reference, particularly page 483). Chen et al report that long term survival of such MM CNS was achieved via the use of a combination of radiation, chemotherapy, and immunomodulatory agents, a “triple modality approach” (see again the entire reference, particularly page 483, as well as page 487, bottom of right column bridging to page 488, top of left column).
In view of the teachings of Chen et al, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the methods suggested by Spencer et al-2, Weaver et al, and Bolli et al so as to have employed the triple therapy taught by Chen et al, including the use of radiation and chemotherapy, in the treatment of MM patients of the type taught by Chen et al, and thereby to have performed methods meeting the requirements of claim 54. An ordinary artisan would have been motivated to have made such a modification for the advantage of improving the survival of such a patient, as taught by Chen et al. It is further noted that an ordinary artisan would have been motivated to have performed such a treatment at whatever point such disease was first diagnosed, including as a first treatment prior to further testing/detection of somatic aberrations (and Chen et al make clear that such disease may be present either at initial diagnosis or relapse). Further, given Chen et al’s reported data, an ordinary artisan would have had a reasonable expectation of success in performing such methods.
Conclusion
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/DIANA B JOHANNSEN/Primary Examiner, Art Unit 1682
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