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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 .
Priority
This application is a continuation of U.S. Patent Application No. 19/096,210, filed March 31, 2025, which is a continuation of U.S. Patent Application No. 17/941,509, filed September 9, 2022, now U.S. Patent No. 12,285,424, which is a continuation of International Application No. PCT/US2021/021713, filed March 10, 2021, which claims the benefit under 35 U.S.C. 119(e) of U.S. Provisional Application No. 62/987,707, filed March 10, 2020.
Claim Status
Claims 31-59 are pending and are examined. Claims 1-30 are canceled
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/15/2025 has been considered by the examiner.
Free of the art
A reasonable and comprehensive search conducted by the Examiner determined that the prior art at the time of the present invention was such that it did not anticipate or render obvious the claimed method. However, the closest prior art is noted to be a combination of Arbeit (WO2017/112894 A1) cited in the IDS dated 07/15/2025 and Dale et al (Curr Opin Hematol. 2017 Janurary;24(1): 46-53) cited in the IDS dated 07/15/2025.
Arbeit teaches a method for treating WHEVI syndrome in a patient in need thereof, comprising administering to said patient X4P-001 or a pharmaceutically acceptable salt or composition thereof, in an amount effective to increase absolute neutrophil count (ANC) to a level greater than or equal to 600/μΙ and/or to increase absolute lymphocyte count (ALC) to a level greater than or equal to 1000/µL. (See claim 15.) The patient originally exhibited ANC less than 600/µL and/or ALC less than 1000/μΙ before treatment with X4P-001. (See claim 16.) That meets the limitation of claim 31. Arbeit teaches the method results in increases in ANC levels to at least about 600/µL on at least 85% of assessments and in increases in ALC to at least about 800 cells/µL, 1000cells/µL, or 1500 cells/µL on at least 85% of assessments; meeting the level of ANC greater than equal to 500/µL and the level of ALC greater than 1000/µl claimed in claim 31. (See claims 18 and 19.) Moreover, Arbeit teaches X4P-001 can be administered at a dose of about 200 mg, or about 300 mg, or about 400 mg once per day. (See paragraph 0056].) Moreover, Arbeit also teaches a single oral dose of X4P-001 at 100 mg/kg, neutrophils to 2.8x and lymphocytes to 1.9x compared to baseline. (Table 5. It is noted that X4P-001 is another name for mavorixafor. (See paragraph [0090]- [0094].) Furthermore, Arbeit teaches patients who may be treated according to the present invention include patients who have been diagnosed with WHIMS or with MKX; and patients who present the characteristic mutations in their CXCR4 gene. Other patients who may benefit from the present invention may include individuals presenting with the following screening criteria:
Neutropenia (ANC <400 or <600/μί) and/or lymphopenia (ALC <650 or
<1000/μΙ.) - the latter is not characteristic of other chronic neutropenias;
Neutropenia and chronic warts;
Myelokathexis on bone marrow aspirate; Patients meeting the above criteria are genetically screened for MKX. Patients with the characteristic mutations in CXCR4 are the most likely to benefit from treatment in accordance with the present invention. (See paragraphs [0091] & [0095].)
Dale teaches Neutropenia is deemed “severe” and “chronic” when the counts are < 0.5 × 109 /L on at least 3 occasions in a 3-month period. It is called “idiopathic” when it cannot be attributed to a drug and there is no definable genetic, infectious, inflammatory, autoimmune or malignant cause. (See Introduction Section.)
The relied-upon paragraphs below in Arbeit do not describe the limitation of the present claims that the patient has not been diagnosed with WHIM or with myelokathexis and does not have a gain-of-function mutation in the CXCR4 gene. One of ordinary skill in the art would not have been motivated to attempt treating patients in accordance with the present claims because said patients fall outside the criteria for all patient groups described in Arbeit. Paragraphs [0091]-[0095], reproduced below use language and grammatical structure requiring that the "other patients who may benefit" must meet the "following screening criteria," (emphasis added) which is the plural of "criterion."
Example 2: Clinical: Patients to be Treated:
[0091] Patients who may be treated according to the present invention include patients who have been diagnosed with WI-IMS or with MKX; and patients who present the characteristic mutations in their CXCR4 gene. Other patients who may benefit from the present invention may include individuals presenting with the
following screening criteria:
[0092] Neutropenia (ANC < 400 or < 600/µl) and/or lymphopenia (ALC < 650 or
< 1000/µL)- the latter is not characteristic of other chronic neutropenias;
[0093] Neutropenia and chronic warts;
[0094] Myclokathexis on bone marrow aspirate;
[0095] Patients meeting the above criteria are genetically screened for MKX.
Patients with the characteristic mutations in CXCR4 are the most likely to benefit from
treatment in accordance with the present invention.
One of ordinary skill in the art would recognize that the use of the plural "criteria" as opposed to the singular "criterion, “suggests that all three criteria of paragraphs [0092]-[0094] must be met for the patient to potentially benefit from X4P-001 treatment under the alleged teachings of Arbeit. Moreover, the inclusion of a semicolon (;) after each criterion and the lack of an "or" operator makes it apparent that the criteria are linked together as members of a list.
Importantly, immediately following the criteria of [0092]-[0094], paragraph [0095] states that "patients meeting the above criteria are genetically screened for MKX." MKX is an abbreviation for myelokathexis (see paragraph [0018] of Arbeit). Myelokathexis is defined as the "trapping of white blood cells in the bone marrow" (Arbeit, paragraph [0021])," and "prolonging the activity of SDF-la dependent signaling [with CXCR4] is the probable cause for myelokathexis." (Arbeit, paragraph [0018]) Myelokathexis (MKX) shares the same gain-of-function CXCR4 mutation that causes WHIMS and, in fact, is the "M" in WHIMS (see e.g., Arbeit paragraph [0001]). In view of this inextricable association between WHIMS and MKX, one of ordinary skill in the art would have read paragraphs [0092]-[0094] of Arbeit as listing an alternative means of identifying WHIMS and MKX patients like those in [0091], who are "diagnosed with WHIMS or with MKX; and who present the characteristic mutations in their CXCR4 gene." Paragraph [0095] repeats for good measure that "patients with the characteristic mutation in CXCR4 are the most likely to benefit from treatment," thus emphasizing the connection between WHIMS, MKX, and gain- of-function CXCR4 mutation. The overlapping and repetitive criteria of [0091]-[0095] nowhere teach patients who exhibit neutropenia without WHIMS/MKX or the CXCR4 gain-of-function mutation. In any event, all patients suggested for treatment by Arbeit are excluded from the scope of the present claims.
Any reliance of the Office on paragraph [0096] of Arbeit, reproduced below, is similarly flawed. Not only does paragraph [0096] use the plural "criteria" in the same way as paragraph [0095], it also explicitly requires both a genotype-confirmed CXCR4 mutation consistent with WHIM syndrome and certain blood ANC and/or ALC levels in addition to one of the findings listed in subparagraph 3:
[0096] Thus, the effects of X4P-001 is expected to be greatest in patients with myelokathexis associated with mutation in CXCR4. In addition, patients who may benefit from treatment according to the present invention include individuals presenting with the following screening criteria:
1. Has a genotype-confirmed CXCR4 mutation consistent with WHIM syndrome; and
2. Has ANC <400 or <600/µL, or ALC <650 or < 1000/µL both, on at least two independent
blood samples collected over a period of up to 14 days.
3. Have one of the following findings:
- A bone marrow aspirate or biopsy showing myelokathexis
- Peripheral WBC counts (>2 independent samples, obtained in the absence of signs or symptoms of acute infection, and when not having received G- or GM-CSF in the past 7 days) showing absolute
neutrophil count <900/µl and/or absolute lymphocyte count <1,500/µl.
Therefore, for at least the reasons above, Arbeit does not teach or suggest to one skilled in the art that mavorixafor would be expected to successfully treat chronic neutropenia in patients who do not have a gain-of-function mutation in the CXCR4 gene and who have not been diagnosed with WHIM/MKX in accordance with the present claims.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 31-59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 12,377,090. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the U.S. patent anticipate the instant claims.
The U.S. patent claims teach a method for treating chronic neutropenia, cyclic neutropenia, or congenital neutropenia in a patient in need thereof, wherein the patient does not have a gain-of-function mutation in the CXCR4 gene and has not been diagnosed with WHIM syndrome or with myelokathexis, comprising administering to the patient an effective amount of mavorixafor:
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or a pharmaceutically acceptable salt thereof; wherein the patient has an absolute neutrophil count (ANC) at or below 1,000 cells/μL at a baseline prior to administering mavorixafor or a pharmaceutically acceptable salt thereof; and the amount of mavorixafor or a pharmaceutically acceptable salt thereof administered is about 200 mg/day, about 300 mg/day, or about 400 mg/day. (See claim 1.) The U.S. patent claims teach the patient has chronic neutropenia, wherein the patient has cyclic neutropenia., wherein the patient has congenital neutropenia, wherein the patient has chronic idiopathic neutropenia (CIN), wherein the patient has autoimmune neutropenia (AIN), wherein the congenital neutropenia is caused by GSD1b, G6PC3 deficiency, GATA2 deficiency, a genetically-defined condition with or without myeloid maturation arrest at the myelocyte/promyelocyte stage, suspected aplastic anemia, B-cell immunodeficiency, or juvenile myelodysplastic syndrome (MDS), wherein the congenital neutropenia is caused by GSD1b due to mutations in SLC37A4; G6PC3 deficiency due to mutations in G6PC3, and GATA2 deficiency due to mutations in GATA2. (See claims 2-8.) Moreover, the U.S patent claims teach the patient has an ANC less than 600 cells/μL at the baseline prior to administering mavorixafor or a pharmaceutically acceptable salt thereof; the patient has an ANC less than 500 cells/μL at the baseline prior to administering mavorixafor or a pharmaceutically acceptable salt thereof; the patient has an absolute lymphocyte count (ALC) less than 1,000/μL at the baseline prior to administering mavorixafor or a pharmaceutically acceptable salt thereof; the patient has an absolute lymphocyte count (ALC) less than 650/μL at the baseline prior to administering mavorixafor or a pharmaceutically acceptable salt thereof.; and the patient has an ANC less than 500 cells/μL and an absolute lymphocyte count (ALC) less than 650/μL at the baseline prior to administering mavorixafor or a pharmaceutically acceptable salt thereof. (See claims 9-13.) The U.S. patent claims also teach the method is effective to increase absolute neutrophil count (ANC) to a level of at least 1,500 cells/μL on at least 85% of assessments; the method is effective to increase absolute lymphocyte count (ALC) to a level of at least 1,500 cells/μL on at least 85% of assessments; the method provides sustained increases in ANC of >600/μL on at least 85% of assessments; the method increases ANC to a level greater than or equal to 1,500 cells/μL in the patient and increases ANC to at least 1.4× the baseline in the patient; method results in an increase in ANC levels to those of a human with a normally functioning immune system, on at least 85% of assessments; the method results in an increase in ALC levels to those of a human with a normally functioning immune system, on at least 85% of assessments. (See claims 14-19.) The U.S. patent claims further teach the patient is not receiving therapy with G-CSF or GM-CSF, or a variant thereof; the patient is receiving therapy with G-CSF or GM-CSF, or a variant thereof; the patient is experiencing adverse effects attributed to the therapy with G-CSF or GM-CSF, or a variant thereof; the patient is currently receiving G-CSF and continues chronic dosing at a dosage sufficient to maintain clinical benefits in a daily amount of about 6 meg/kg (for patients having congenital neutropenia); about 2.1 meg/kg (for patients having cyclic neutropenia); or about 1.2 mcg/kg (for patients having idiopathic neutropenia). (See claims 20-24.) Lastly, the U.S. patent claims teach mavorixafor is administered at a dose of 200 mg/day; mavorixafor is administered at a dose of 300 mg/day; mavorixafor or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 mg/day; mavorixafor is administered at a dose of 400 mg/day; and the method results in at least 25% reduced frequency of infections. (See claims 25-28.)
Claims 31-36, 39-52, and 56-59 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 12,285,424. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the U.S. patent anticipate the instant claims.
The U.S. patent claims teach a method for treating chronic neutropenia, cyclic neutropenia, or congenital neutropenia in a patient in need thereof, wherein the patient does not have a gain-of-function mutation in the CXCR4 gene, comprising administering to the patient an amount of mavorixafor:
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or a pharmaceutically acceptable salt or composition thereof effective to increase absolute neutrophil count (ANC) to a level greater than or equal to 500 cells/μL and absolute lymphocyte count (ALC) to a level greater than 1000 cells/μL in the patient;
wherein the patient has an absolute neutrophil count (ANC) less than 500 cells/μL at a baseline prior to administering mavorixafor or a pharmaceutically acceptable salt or composition thereof;
the amount of mavorixafor or a pharmaceutically acceptable salt or composition thereof administered is about 200 mg/day, about 300 mg/day, or about 400 mg/day;
the patient has not been diagnosed with WHIM syndrome or with myelokathexis; and
wherein the method results in an increase of ANC to at least 2.0 x the baseline. (See claim 1.) The U.S. patent claims teach the patient has chronic neutropenia, wherein the patient has cyclic neutropenia., wherein the patient has congenital neutropenia, wherein the patient has chronic idiopathic neutropenia (CIN), wherein the patient has autoimmune neutropenia (AIN). (See claims 2.) The U.S. patent claims teach mavorixafor is administered at a dose of 300 mg/day; mavorixafor or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 mg/day. (See claims 4-5.) The U.S. patent claims further teach the method is effective to increase absolute neutrophil count (ANC) to a level of at least 800 cells/μL on at least 85% of assessments; the method is effective to increase absolute lymphocyte count (ALC) to a level of at least 1,500 cells/μL on at least 85% of assessments; and mavorixafor or a pharmaceutically acceptable salt thereof is administered at a dose of 200 mg/day. (See claims 6-8.)
With respect to the sustained release limitations of claims 47-5; these limitations simply express the intended outcome of the method step positively recited. Since the method step claimed is the same as the method step taught by the U.S. patent, said limitations are necessarily present absent evidence to the contrary.
Conclusion
Claims 31-59 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628