Methods for Treating Multiple Myeloma

§101 §103

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 . Election/Restrictions Applicant’s election without traverse of group II, claims 23, and species (A) translocation after the translation start site, (B) truncated NSD2 protein length, which according to the specification is after genomic position 1,900,655 of GRCh38.p133, and (C) small molecule as the NSD2 inhibitor, in the reply filed on August 18, 2026 is acknowledged. Claims 1-7, 10, 12, 14, 16-22, and 24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 23 and new claims 46-51 are under consideration in this office action. Priority Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The application is the national stage entry of PCT/US2022/017844, which claims benefit to U.S. Provisional Application No. 63/154,104, filed February 26, 2021. Information Disclosure Statement The information disclosure statements (IDSs) submitted on March 18, 2024, April 29, 2025, and August 18, 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDSs are being considered by the examiner. Claim Objections Claim 49 objected to because of in claim 49, line 1, there is a comma and space missing after “claim 23”. Appropriate correction is required. Claim Rejections - 35 USC § 101 35 U.S.C. 101 reads as follows: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title. Claims 23 and 46-51 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. Under Step 1 of the 2019 Revised Patent Subject Matter Eligibility Guidance the claimed method is found to be drawn to one of the four statutory categories of inventions, a process. Under Step 2A, prong 1, the claims have been determined to recite a law of nature/a natural relationship and a mental process. Natural relationships are laws of nature that have been deemed ineligible subject matter because methods directed to the natural relationship without significantly more, preempt use of the natural relationship itself. Here, the claims involve the natural relationship where the presence of 4:14 chromosome translocation determines whether a subject is selected for treatment with the NSD2 inhibitor. A claim recites a mental process if it is directed to collecting and comparing known information, which are steps that can be practically performed in the human mind [see Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1067, 100 USPQ2d 1492, 1500 (Fed. Cir. 2011)]. The claims recite the judicial exceptions natural phenomenon and mental process (STEP 2A, Prong One: YES). The invention as a whole is directed to judicial exceptions and thus required further analysis at Step 2B to determine if the claims amount to significantly more than the exception itself. Under Step 2A, prong 2, the claims have been determined to not recite additional elements that integrate the judicial exception into a practical application, i.e., the claims do not use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that the claim is more than a drafting effort designed to monopolize the exception. It is well established that the mere physical or tangible nature of additional elements, such as the obtaining and detecting of steps, does not automatically confer eligibility on a claim directed to a natural phenomenon [see, e.g., Alice Corp v. CLS Bank Int’l, 134 S. Ct. 2347, 2358-59 (2014)]. MPEP section 2106.04(d) recites further consideration for integration of a judicial exception to a practical application. Relevant considerations include an improvement in the technical field; applying the judicial exception to effect a particular treatment or prophylaxis for disease; implementing the judicial exception with a particular machine; effecting a transformation to a different state or thing; and, applying or using the judicial exception in some meaningful way beyond generally linking the use to a technological environment. In the instant case, the additional steps of determining whether the subject has a 4:14 chromosome translocation that results in a disruption of the NSD2 gene and selecting the subject for treatment with an NSD2 inhibitor offer no improvement in the technology. These steps were well understood, routine and convention in the art at the time of filing. The courts have found that arranging a hierarchy of groups is to be well-understood, routine, conventional activity when they are claimed at a high level of generality Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1331, 115 USPQ2d 1681, 1699 (Fed. Cir. 2015) (see MPEP 2106.05(d)). Therefore, these steps do not relate to the natural principles in a significant way to impose a meaningful limit on the scope. Note that the Supreme Court in Mayo v. Prometheus has made clear that to transform an unpatentable law of nature into a patent-eligible application of such a law, one must do more than simply state the law of nature while adding the “apply it.” Essentially, appending conventional steps or at a high level of generality to laws of nature, natural phenomena, and abstract ideas cannot make those laws, phenomena, and ideas patent-eligible. In Prometheus, the court found that “[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself.” Additionally, “conventional or obvious”” “[pre]solution activity” is normally not sufficient to transform unpatentable law of nature into a patent-eligible application of such a law”. Flook, 437, U.S., at 590; see also Bilski, 561 U.S., (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’…, adding ‘insignificant post-solution activity’” (quoting Diehr, supra, at 191-102). The required steps are merely the extra solution activity that must be performed in order to observe the natural phenomenon itself. As a whole, the additional steps/elements do not apply the judicial exception in any meaningful way. (STEP 2A, Prong Two: NO). Under final Step 2B, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception encompassed by the method of the instant claims, i.e. the claims do not recite elements beyond the well-understood, routine, or conventional activities previously known to the field. In the instant claims, the elements in addition to the natural relationship are a 4:14 chromosome translocation that results in disruption that is located after the translation start site of NSD2 and treatment with an NSD2 inhibitor. These steps are recited at a high level of generality, the breadth of which reads upon practices that are routinely performed, such as detecting the translocation and selecting the patient population to be treated. Further, the determination of whether the translocation results in a disruption of the NSD2 gene and whether the subject will benefit from NSD2 inhibitor treatment are directed to a mental process that can be performed using routine and conventional methods. 4:14 chromosome translocation in patients with multiple myeloma are well described in the prior art. See US 20110207198 published August 25, 2011 (“Chinnaiyan”; IDS from 3/18/2024), which teaches that patients with MMSET involvement in t(4;14) chromosomal translocation experience a 15% rate of recurrence and worsened prognosis in comparison to multiple myeloma patients lacking such translocation [0010]. This translocation is associated with disruption in the NSD2 gene and these patients with this translocation are responsive to NSD2 inhibitor therapy ([0103,[0208]. Also see WO 2020037079 published February 20, 2020 (“Lampe”; IDS from 3/18/2024), which teaches a method of identifying whether a subject having multiple myeloma is a candidate for treatment with a compound, the method comprising: (a) determining whether a t(4,14) chromosomal translocation is present or absent in a biological sample taken from the subject with multiple myeloma; and (b) identifying the subject as being a candidate for treatment if a chromosomal translocation is present ([0016],[0374], [0443]). Thus, the prior art establishes that the steps and elements recited in addition to the judicial exception of the claims were all well understood, routine, and conventional prior to filing. For all of these reasons, the additional elements do not amount to significantly more than the exception itself (STEP 2B: NO). The preponderance of evidence demonstrates that the claims are not directed to patent eligible subject matter, and claims 23 and 46-51 are rejected under 35 U.S.C. 101. 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. 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. Claims 23 and 46-51 are rejected under 35 U.S.C. 103 as being unpatentable over US 20110207198 published August 25, 2011 (“Chinnaiyan”; see IDS from 3/18/2024) WO 2020037079 published February 20, 2020 (“Lampe”; see IDS from 3/18/2024) Li et al published May 24, 2017 (instant PTO-892). Chinnaiyan teaches that NSD2 (also known as MMSET) is a histone methyltransferase that is aberrantly expressed in patients with multiple myeloma. Patients with MMSET involvement in t(4;14) chromosomal translocation experience a 15% rate of recurrence and worsened prognosis in comparison to multiple myeloma patients lacking such translocation [0010]. MMSET is overexpressed in some cancers [0010], and inhibition of this enzyme with small molecule inhibitors has therapeutic impact ([0103],[0208]). Chinnaiyan does not explicitly teach a method of selecting a patient for treatment with the NSD2 inhibitor based on the genomic position of the translocation. Lampe teaches a method of identifying whether a subject having multiple myeloma is a candidate for treatment with a compound, the method comprising: (a) determining whether a chromosomal translocation is present or absent in a biological sample taken from the subject; and (b) identifying the subject as being a candidate for treatment if a chromosomal translocation is present [0016],[0443], as in instant claim 23. The chromosomal translocation in multiple myeloma is a t(4,14) translocation [0374]. Lampe teaches that subjects with t(4; 14) demonstrate an overall poor prognosis that is only partially mitigated using existing chemotherapeutic agents [0439]. Lampe teaches that a biological sample can be analyzed for chromosomal translocations using polymerase chain reaction (PCR) methodology, reverse transcription-polymerase chain reaction (RT-PCR) methodology, or cytoplasmic light chain immunofluorescence combined with fluorescence in situ hybridization (clg-FISH) [0573], as in instant claim 51. Li et al evaluated whether over expression of full-length or truncated forms of MMSET (also known as NSD2) influence the prognosis of t(4;14) chromosome translocation positive multiple myeloma patients (abstract). Li et al teach that patients with truncated forms of MMSET (subgroups MBR-2 and MB4-3) exhibited poorer prognosis than patients with full-length MMSET (MB4-1), as in instant claims 46-47 and 50. Truncated forms of MMSET that lack exons 3 or exons 3 or 4 are localized differently than full length MMSET, with truncated forms accumulating in the nucleus and nucleoli, potentially with stronger cancer-causing force (pg 51615, column 2, para 1). Reproduced below is a schematic representation of the t(4;14) junction, der(4), showing the three different types of 4p16.3 breakpoints (MB4-1, MB4-2, and MB4-3) (Figure 1). Rectangle with “3” represents the first coding exon of MMSET. PNG media_image1.png 176 960 media_image1.png Greyscale The translocations of subgroups MB4-2 and MB4-3 meet the limitation of claim 23 drawn to a translocation that results in a disruption of the NSD2 gene that is located after the translation start site of NSD2. The translocation of the MB4-2 subgroup is located between the start of the first coding exon and the start of the second coding exon of the NSD2 gene, as in instant claim 47. The translocation of Li et al results in expression of truncated NSD2 protein (abstract). Regarding the genomic positions of instant claims 48-49, exon 3 starts at 1,904,000, exon 4 starts at 1,917,500, and exon 5 starts at 1,918,000 (as evidenced by UCSC Genome Browser, instant PTO-892). GRCh38/hg38 shown below, darks bars are, in order, noncoding exon 2 and coding exons 3-6. PNG media_image2.png 517 1500 media_image2.png Greyscale Li et al teaches chromosomal translocations after the translation start site of NSD2 gene and its relationship to prognosis in t(4;14) chromosome translocation positive multiple myeloma patients and would therefore have provided a skilled artisan with a reason to determine the presence of truncated NSD2 when selecting patients for treatment with an NSD2 inhibitor. Given that Chinnaiyan teaches treatment of patients with NSD2/MMSET t(4;14) chromosomal translocation with NSD2 inhibitor, and further given that Lampe teaches a method of selecting a patient for a treatment based on whether the t(4;14) chromosomal translocation is present or absent and Li et al teaches specific chromosomal translocations in NSD2 gene and related truncated forms with poorer prognosis, it would have been obvious to one of ordinary skill in the art to apply the patient-selecting method of Lampe in the patient of population of Li et al with the NSD2 inhibitor of Chinnaiyan, because doing so would constitute the application of known patient-selection techniques to a known disease-associated genetic population for treatment with a known therapeutic agent. The motivation to do some comes from Li et al, which teaches that overexpression of MMSET/NSD2 of truncated forms of NSD2 is associated with worse outcomes. Such would amount to the combining of prior art elements (inhibitor of Chinnaiyan and t(4/14) translocation of Li et al in multiple myeloma) with a known method (the selecting method of Lampe) to yield predictable results, see MPEP 2143. Conclusion No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER BENAVIDES whose telephone number is (571)272-0545. The examiner can normally be reached M-F 9AM-5PM (EST). Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at (571)272-0911. 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