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 .
Current Status of 17/786,912
This Office Action is responsive to the amended claims of 09/11/2025. Claims 1, 4, 6, and 9-29 have been examined on the merits.
Priority
The instant application is a national stage entry of PCT/US2020/066099, international filing date 12/18/2020, which claims priority to U.S. Provisional Patent Application No. 62/949,968, filed 12/18/2019.
Response to Arguments
Applicants have cancelled claims 2, 3, 5, 7, and 8. Claims 7-28 were objected to in the Office Action mailed 03/12/2025 for being improperly multiple dependent claims. Applicants have amended claims 9-28 to correct this issue, rendering the previous objection moot. This objection is withdrawn.
Applicants have amended claim 29 to include antecedent basis for the abbreviation of Waldenstrom's macroglobulinemia (WM) in the claim. This amendment renders the objection moot and the objection is withdrawn.
101 Rejection
Applicants have amended claim 29 to make the claim a method of treating WM comprising a method for patient selection (steps (a) and (b)) and a method to effect treatment (c). These amendments make the claimed method patentable under 35 U.S.C. §101 and the previous rejection is withdrawn.
102 Rejections
Applicants' arguments have been fully considered but are not persuasive. As amended, the claims no longer read on the disclosure of Treon for anticipation. Accordingly, the previous rejection under 35 U.S.C. §102 is withdrawn. However the amendments introduce additional treatment steps that are taught or suggested by the prior art of record, and the claims are now rejected under 35 U.S.C. §103, as set forth below.
103 Rejections
Applicants' arguments have been fully considered but are not persuasive. Applicants argue that B49 and Cao fail to provide a finite number of identified, predictable solutions and further contend that the artisan would lack a reasonable expectation of success in arriving at the claimed combination therapy. Applicants rely on In re Kubin in support of these assertions and additionally allege that WM is not exemplified by B49, that in vitro data of Cao are insufficient to support a therapeutic expectation of success, and that the artisan would have used AMD3100 rather than X4P-001 based on its approval status.
First, Applicants incorrectly assert that claim 1 requires treatment of a "human patient." The term does not appear in the claims and the specification explicitly defines "patient" to include both human and non-human subjects, with humans merely being a preferred embodiment (see [00123]). Arguments directed to "human patient" limitations are not commensurate with the scope of the claims.
Applicants' arguments about the teachings of B49 lacking a finite number of predictable, identified solutions is not persuasive nor is the characterization that the reference's disclosure gives only general guidance. The method of treating WM by administering X4P-001 is described beginning at [00166] and continues through [00174]. These sections of the reference disclose the administration of an effective amount of X4P-001 to a patient alone or in combination with one or more standard of care treatments for WM. The standard of care chemotherapies are selected from chlorambucil, cladribine, cyclophosphamide, fludarabine, bendamustine, and ibrutinib. The list of standard care chemotherapies repeats twice in [00167] and [00173] and after each instance ibrutinib is disclosed as the additional therapeutic agent. Additionally, Table 5 discloses exemplary dosing regimens for ibrutinib. Taken together, these disclosures constitute a clear and direct teaching that would guide the artisan to administer X4P-001 in combination with ibrutinib for the treatment of WM.
Cao provides a clear mechanistic rationale: CXCR4 WHIM-like mutations drive ibrutinib resistance in WM, and CXCR4 inhibition restores sensitivity to BTK inhibition. This is a direct motivation to combine a CXCR4 inhibitor with ibrutinib in mutation-positive WM patients with a reasonable expectation of success. Applicants' assertions regarding in vitro studies do not overcome this teaching. Obviousness does not require clinical data or certainty of success.
Applicants' arguments regarding AMD3100 is similarly unpersuasive. B49 explicitly discloses X4P-001 as a CXCR4 inhibitor suitable for treating cancer, including hematological malignancies and discloses WM as a species of this genus. FDA approval status is not required for obviousness, nor does regulatory approval determine what the artisan would consider for combination therapy. The art provides both the motivation and expectation of success for using XP4-001 in the claimed methods.
Applicants' arguments do not overcome the teachings of B49 and Cao and the rejection under U.S.C. §103 is maintained.
Applicants' arguments of the rejection of claims 29 and 30 in view of Treon and B49 have been fully considered but are not persuasive. As previously noted, Applicants have amended claim 29 in a manner that significantly alters the scope of the claimed invention. Much of Applicants' present arguments rely on the limitations introduced by the amendments, and therefore cannot rebut the teachings of the art as applied to the originally presented claims.
Applicants again assert that claim 29 requires a "human patient," despite the fact that this phrase does not appear anywhere in the claim. The argument is therefore premised on a requirement that does not exist in the claim language and is not persuasive.
The teachings of B49 and Cao are discussed above and are incorporated by reference into this response. The combined references teach a method of treating WM through administering X4P-001 in combination with ibrutinib. The references additionally provide motivation for targeting the specific mutations claimed.
Applicants' remaining arguments focus on the alleged deficiencies of Treon. Applicants allege that the teachings of the reference are limited in scope due to the reliance on in vitro studies using two cell lines engineered to express either CXCR4WT or CXCR4S338 and contend that such assays constitute early-stage discovery tools that do not provide a reasonable expectation of success in treatment. These arguments are not persuasive. Treon explicitly teaches evaluating patient responsiveness based on the presence of the same CXCR4 and MYD88 mutations recited in the amended claims and describes how CXCR4 inhibition may restore sensitivity to standard WM therapies. The use of engineered cell lines to isolate the functional consequences of specific somatic mutations is a well-established and routine methodology in the art (see Luo et al). Such systems are commonly employed to elucidate mutation-driven signaling, drug response, and therapeutic targeting. The fact that the CXCR4S338 mutation was introduced by lentiviral transduction does not diminish the relevance of the findings. Rather, the findings isolate the direct biological effect of the mutation and provides mechanistic insight that informs therapeutic expectations. The reference therefore provides a clear motivation and a reasonable expectation of success for detection of the mutations.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 21, 22, and 24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, the phrase "optionally" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 21 recites the limitation "IgM from baseline" in the second line of the claim. There is insufficient antecedent basis for this limitation in the claim. Claim 1 does not introduce IgM nor is there a step involving IgM measurement in the claim.
Regarding claim 22, the phrase "non-diseased adult human (non-WM patient)" renders the claim indefinite because it is unclear whether the limitation following the phrase are part of the claimed invention. As written, it is unclear whether the non-diseased adult human is free of all disease or if they are only free from WM.
Regarding claim 24, the limitation requiring that “the dose of ibrutinib…is decreased by at least 20% relative to the effective dose of ibrutinib as a monotherapy” is indefinite because the claim does not define what constitutes the “effective dose of ibrutinib” serving as the reference point. As written, the reference point for calculating the claimed 20% reduction is undefined, and the scope of the claims cannot be determined with reasonable certainty.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 4, 6, 9-20, and 25-28 are rejected under 35 U.S.C. 103 as being unpatentable over B49 (WO 2018237158-A1, found in IDS filed 10/062022) in view of Cao (Cao, Y., et al. "The WHIM-like CXCR4S338X somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom’s Macroglobulinemia." Leukemia 29.1 (2015): 169-176. Found in IDS submitted 10/06/2022).
Paragraphs [00166]-[00174] of B49 disclose a method of treating WM in a patient in need thereof, comprising administering to the patient an effective amount of X4P-001 optionally in combination with one or more standard of care treatments, or a combination thereof for WM (Para. [00166]). The standard of care chemotherapy treatments disclosed are chlorambucil, cladribine, cyclophosphamide, fludarabine, bendamustine, and ibrutinib in paragraphs [00167] and [00173]. Ibrutinib is also disclosed independently following these lists of standard of care chemotherapies as an additional therapeutic agent. B49 teaches that the combination therapy comprising X4P-001 and optionally another therapeutic agent across all lines of therapy, including first-line [00168], second-line [00170], and third-line treatment [00171], as well as in settings where the disease has become resistant or desensitized to prior chemotherapy [00169]-[00172].
The reference also teaches that X4P-001 can act as a sensitizer that enhances the efficacy of standard of care therapies including, first-, second-, or third-line chemotherapy or immunotherapy. X4P-001 is stated to improve patient responsiveness or restore sensitivity to standard therapies [00172].
The reference reiterates that X4P-001 may be used in combination with additional therapeutic agents, again listing the same standard of care chemotherapies and expressly naming ibrutinib as an additional therapeutic agent suitable for co-administration [00173]. Dosing information for ibrutinib is also disclosed in Table 5 of [00174].
B49 teaches administering X4P-001 in combination with ibrutinib for the treatment of WM. These teachings apply broadly to WM and do not exclude patients bearing the specific CXCR4 mutations recited in the instant claims, as the reference is silent regarding these mutations. However, reference Cao directly addresses the functional consequences of WHIM-like CXCR4 gain-of-function mutations and provides additional motivation for the skilled artisan to apply the disclosed combination regimen to WM patients harboring the claimed mutations.
Cao teaches that MYD88 L265P and CXCR4 mutations are the most prevalent somatic mutations in Waldenstrom’s Macroglobulinemia and that CXCR4(S338X) is the most common somatic mutation (page 169, left column) reading on claims 4-6. Cao also teaches that pAKT a pERK are enhanced in SDF-1a-stimulated CXCR4(S338X) compared to CXCR4(WT) WM cells, this enhancement is a gain of function mutation (page 173, left column). Cao additionally teaches a mutation comprising a WHIM-like mutation that results in a gain of function in CXCR4 relative to CXCR4(WT) (page 169, left column; page 173, left column). Cao teaches that the use of inhibitors targeting CXCR4 can restore the sensitivity of CXCR4(S338X)-expressing WM cells to ibrutinib as well as other WM relevant agents, thereby providing a framework for the investigation of these combinations in WM (page 176, left column).
B49 teaches the method of treating WM using X4P-001 in combination with ibrutinib and does not limit the treatment based on the CXCR4 genotype of patients. Cao provides mechanistic rationale for applying this established regimen specifically to patients harboring the WHIM-like CXCR4 mutations recited in the instant claims. In view of these teachings, the artisan would have been motivated to adapt the combination therapy of B49 to WM patients with the claimed CXCR4 mutations and would have reasonably expected that co-administration of a CXCR4 inhibitor such as X4P-001 with ibrutinib would overcome mutation driven resistance and improve treatment responsiveness. This makes obvious the claimed method of instant claims 1, 4, and 6.
The additional claim limitations imposed by instant claims 9 and 11 requiring prior treatment with either a BTK inhibitor or ibrutinib, respectively, are also rendered obvious by the cited references. B49 teaches that ibrutinib and other BTK inhibitors are standard of care therapies for WM [00167] and further teaches administering X4P-001 as a second- or third-line treatment when standard therapies fail or when the disease becomes resistant [00169]-[00171]. As such, a patient receiving X4P-001 in second- or third-line settings would inherently have previously received at least one course of first-line treatment, which includes BTK inhibitors, such as ibrutinib. Likewise, the additional limitation of instant claim 12 requiring that the patient’s WM “has shown disease progression” is also obvious, as B49 teaches administering X4P-001 in second- and third-line setting when standard therapies fail or the disease develops resistance, which inherently identifies patients whose WM has progressed.
The limitation of instant claim 10 requiring that “the patient’s WM is resistant to treatment with a BTK inhibitor” is also rendered obvious by the cited references. B49 teaches administering X4P-001 as a second- or third-line therapy when standard of care treatments fail or when the disease becomes resistant [00169-[00171]. Because BTK inhibitors, including ibrutinib, are expressly identified in B49 as first-line standard of care therapies for WM, a patient receiving X4P-001 in the resistant second- or third-line settings described in B49 would inherently include those whose WM is resistant to BTK inhibitor treatment.
The claim limitations of instant claims 13-16, which recite specific dosages for X4P-001 and single daily dose administration are similarly obvious in view of the teachings of the references. Example 5 of B49 [00409] discloses administering X4P-001 in dosages ranging from 200 mg to 1200 mg and discloses once daily administration. The disclosed dosage ranges of B49 overlap with those of the instant claims rendering the claimed dosage regimens prima facie obvious.
The limitations of instant claims 17-19, which recite dosage ranges for ibrutinib, are likewise rendered obvious in view of the teachings of the references. Table 5 of B49 ( [00174]) discloses an exemplary dosing regimen for ibrutinib of 420 mg administered orally once daily for treatment of WM until disease progression or unacceptable toxicity. The dosage disclosed in B49 overlaps with the dosage ranges recited in the instant claims and therefore renders the claimed dosage limitations prima facie obvious. Instant claim 20 recites a combined dosage regimen for X4P-001 and ibrutinib. Because the individual dosage ranges for each agent are taught by B49, and their combination is already disclosed by the reference as a treatment method, the combined regimen of claim 20 is obvious for the same reasons discussed above.
Claims 25-28 are unpatentable over B49. Paragraph [0042] explicitly teaches that any of the disclosed treatment methods may further include obtaining a biological sample from the patient and measuring the amount of disease related biomarker, thereby meeting the limitation of instant claim 25. Paragraph [0043] teaches that the biological sample may be a blood sample, meeting the limitation of instant claim 26. Paragraph [0044] teaches that the disease-related biomarker may be circulating CD8+T cells or the ratio of CD8+T cells:Treg cells, satisfying instant claim 27. Paragraph [0045] lists WM among the cancers for which the biomarker method is applicable. Although the reference does not explicitly disclose IgM and HgB as biomarkers for this method, in the context of WM they are well-recognized disease biomarkers routinely measured in clinical practice (see Treon, Steven P. “XIII. Waldenström's macroglobulinaemia: an indolent B-cell lymphoma with distinct molecular and clinical features.” Hematological oncology vol. 31 Suppl 1 (2013): 76-80. doi:10.1002/hon.2071). Accordingly, measuring IgM and/or Hgb as recited in claim 28 would have been an obvious choice of biomarker measurement within the framework of B49.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over B49 in view of Cao, and Treon (US 2016/0222465 A1, found in IDS submitted 10/06/2022).
The teachings of B49 and Cao are discussed above and are incorporated by reference into this rejection. B49 teaches treating WM with X4P-001, including in combination with ibrutinib, in first-, second-, and third-line settings, particularly where the disease is resistant or refractory. Cao explains that WHIM-like CXCR4 gain of function mutations confer reduced sensitivity to BTK inhibitors and that CXCR4 inhibition can overcome this resistance and restore treatment efficacy. This provides a clear motivation for why the artisan would select such mutation positive patients for CXCR4 directed therapy.
Treon teaches a method for evaluating a subject’s likely responsiveness to treatment with various therapies [0012] comprising (a) testing a biological sample taken from the patient for a CXCR4 mutation and optionally a MYD88 mutation. [0012] of Treon teaches a method for evaluating a subject having Waldenstrom’s macroglobulinemia (WM) involving obtaining diseased B cells from the subject and performing and assay on the diseased B cells to determine if the diseased B cells contain a mutation in the carboxyl-terminal cytoplasmic tail of the gene encoding CXCR4. Treon also teaches (b) if the patient’s WM bears at least one CXCR4 mutation, selecting the patient for treatment with a CXCR4 inhibitor [0020]. [0009] of Treon teaches WHIM-like mutations to CXCR4 were present as somatic mutations in WM and were predictive of whether various WM therapies, including BTK inhibition treatment would be successful and that CXCR4 inhibition treatment when combined with BTK inhibition treatment, could restore the ability to treat WM successfully even in the presence of CXCR4 mutation.
Based on the combined teachings of the references above, it would have been obvious to the artisan to (a) test the patient for CXCR4 and MYD88 mutations, (b) identify mutation positive WM patients expected to respond poorly to BTK inhibition, and (c) treat such patients with the combination therapy of X4P-001 and ibrutinib as taught by B49, with Cao providing motivation for treating the specific mutant genotypes of CXCR4 and Treon providing the diagnostic framework for determining the mutation status of patients. The combined teachings of these references teach or suggest each element of the amended claim and renders the claimed method obvious.
Conclusion
Claims 1, 4, 6, 9-22, and 24-29 are rejected. Claim 23 is objected to for being dependent upon a rejected base claim.
Applicant's amendments necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625