DETAILED ACTION
Claims 1-19 are pending in the instant application and being examined on the merit.
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 .
Information Disclosure Statement
The information disclosure statement filed 5/15/2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered. This objection specifically refers to the following foreign documents and non-patent literature documents listed below:
Cite No. BA-BT1 (Foreign patent documents);
Cite No. CA-CB8, CQ8, and CX8 (Non-patent literature documents).
Drawings
The drawings are objected to because:
The graphs depicted in figures 7B, 7C, 8A, 12B, 12C, and 16 are partially obscured, rendering the full scope of the graph illegible (See MPEP 608.02).
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
InfinicytTM should read InfinicytTM (page 33, line 30).
Appropriate correction is required.
The use of the terms FACSCaliburTM, Alexa Fluor®, VECTASHIELD®, LEICA®, RNeasy®, TaqMan®, truChIP®, SYBR®, Xenogen®, IVIS®, Matrigel®, LymphoprepTM, and GraphPad Prism® which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. All trademark referenced herein should be identified as such with the appropriate notation:
FACSCaliburTM (page 33, line 29; page 36, line 18);
Alexa Fluor® (page 34, line 22; page 36, line 17);
VECTASHIELD® (page 34, line 25);
LEICA® (page 34, line 26);
RNeasy® (page 34, line 28);
TaqMan® (page 34, line 30);
truChIP® (page 35, line 4);
SYBR® (page 35, line 9);
Xenogen® (page 35, line 20);
IVIS® (page 35, line 20);
Matrigel® (page 35, line 28; page 37, line 23);
LymphoprepTM (page 36, line 28); and
GraphPad Prism® (page 38, line 15).
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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.
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 1-8, 12-15, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Chen (US20110269706 A1, Priority to January 23, 2009, IDS entered on 5/15/2024; hereinafter Chen) and further in view of Garcia-Guerrero (Garcia-Guerrero et al, “Upregulation of CD38 expression on multiple myeloma cells by novel HDAC6 inhibitors is a class effect and augments the efficacy of daratumumab”, April 29 2020, Leukemia, 35:201-214; hereinafter Garcia-Guerrero).
Regarding instant claims 1-8, 13-15, and 17, Chen teaches a method of treating a neoplastic disorder (e.g. cancer) comprising administering to a subject in need thereof an effective amount of a compound, composition and/or salt, wherein the compound comprises the following chemical structure of compound CY190602(hydroxamine derivative of Bendamustine), shown below:
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, wherein the neoplastic disease is multiple myeloma (page 7, ¶ [0017] and ¶ [0020]; page 27, ¶ [0053]; page 9, third chemical structure from the bottom; pages 53-54, ¶ [0205]). This compound (shown above) has the identical chemical structure of tinostamustine as shown in the Specification on page 17, wherein it states that it is also known in the art as EDO-S101. Chen also teaches that the anti-tumor activities of CY190602 (tinostamustine) in many cancer cell lines are significantly better than its parental drug Bendamustine (page 4, ¶ [0010]; page 54, ¶ [0205], Tables on the left column and ¶ [0207], Table on the right column). Chen further teaches that CY190602 (tinostamustine) is a potent histone deacetylase (HDAC) inhibitor, wherein CY190602 inhibited multiple subtypes of HDAC (page 54 ¶ [0205]). Chen also discloses a pharmaceutical composition for the treatment of neoplastic disorders comprising a therapeutically effective amount of the hydroxamic compound described herein (page 6, ¶ [0015], page 30, ¶ [0097]).
However, Chen does not teach a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of tinostamustine in combination with a therapeutically effective amount of the anti-CD38 antibody, daratumumab, wherein the cancer is capable of expressing CD38 upon contacting tinostamustine.
The deficiency is resolved by Garcia-Guerrero.
Garcia-Guerrero teaches that clinical observations with the anti-CD38 antibody, daratumumab, disclosed that the expression of CD38 on pretreated multiple myeloma (MM) cells correlates with efficacy and that patients with higher CD38 expression are more likely to respond to the antibody treatment. However, during daratumumab therapy, CD38 expression levels on MM cells decline, thus favoring immune escape and disease progression. Therefore, Garcia-Guerrero discloses that an increase in the density of CD38 molecules on MM cells is likely to improve response rates and response durability of daratumumab treatment and prevent immune escape (page 202, left column, second paragraph). In this context, Garcia-Guerrero disclosed that ricolinostat (ACY-1215), a specific inhibitor of HDAC6 with potential antineoplastic activity, was used in combination with daratumumab, wherein ricolinostat alone increased CD38 RNA expression and surface CD38 protein expression on MM cells (page 203, §Ricolinostat increases CD38 expression on myeloma cells; Fig. 1), and pretreatment of MM cells with the HDAC inhibitor followed by treatment with daratumumab increased CD38 expression on MM cells, and thus enhanced anti-MM efficacy of daratumumab through a substantial increase in ADCC (page 205, right column-page 208, left column, §Synergistic anti-myeloma efficacy of ricolinostat and daratumumab; Fig. 4). Garcia-Guerrero further teaches that this synergistic effect was also present with other second generation HDAC inhibitors (page 208, right column, §Upregulation of CD38 expression on multiple myeloma cells by novel HDAC6 inhibitors is a class effect), suggesting that the use of HDAC6 inhibitors in general with daratumumab will synergistically increase response rates and extend response duration in MM patients (page 211, right column, last paragraph).
Regarding instant claims 1-8, 13-15, and 17, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method of treating multiple myeloma comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising tinostamustine as taught by Chen to further comprise administering daratumumab in combination, wherein tinostamustine is administered prior to daratumumab to induce CD38 expression in the cancer as taught by Garcia-Guerrero. This is obvious because, Chen teaches a method of treating multiple myeloma comprising administering to a subject in need thereof an effective amount of CY190602 (also known as EDO-S101 and tinostamustine), wherein tinostamustine displayed significantly better anti-tumor activities of tinostamustine in many cancer compared to its parental drug Bendamustine and acted as a potent HDAC pan inhibitor, and Garcia-Guerrero teaches that treatment of MM cells with HDAC inhibitors increased CD38 expression on MM cells, and MM cells that were pretreated with HDAC inhibitors (e.g. ricolinostat) followed by treatment with daratumumab displayed enhanced anti-MM efficacy of daratumumab through a substantial increase in ADCC. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating multiple myeloma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising the combination of tinostamustine and daratumumab, wherein the cancer is capable of expressing CD38 upon contacting tinostamustine.
Regarding instant claim 12, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method of treating multiple myeloma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of tinostamustine in combination with a therapeutically effective amount of daratumumab, wherein the cancer is capable of expressing CD38 upon contacting tinostamustine as taught by the combined teachings of Chen and Garcia-Guerrero to further comprise that the expression of CD38 in cancer cells is low as taught by Garcia-Guerrero. This is obvious because, the combined teachings of Chen and Garcia-Guerrero teach a method of treating multiple myeloma comprising administering to a subject in need thereof an effective amount of tinostamustine, a potent HDAC inhibitor, and daratumumab, wherein the cancer expressed increased CD38 upon treatment with HDAC inhibitors, and Garcia-Guerrero teaches that during daratumumab monotherapy, CD38 expression levels on MM cells decline, thus favoring immune escape and disease progression. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating multiple myeloma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of tinostamustine in combination with a therapeutically effective amount of daratumumab, wherein the expression of CD38 in cancer cells is low, and the cancer is capable of expressing CD38 upon contacting tinostamustine.
Claims 9, 10 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Chen (US20110269706 A1, Priority to January 23, 2009, IDS entered on 5/15/2024; hereinafter Chen) and Garcia-Guerrero (Garcia-Guerrero et al, “Upregulation of CD38 expression on multiple myeloma cells by novel HDAC6 inhibitors is a class effect and augments the efficacy of daratumumab”, April 29 2020, Leukemia, 35:201-214; hereinafter Garcia-Guerrero), as applied to claims 1 and 13 above, and further in view of Mehrling (US11,896,583 B2, Priority to June 13, 2017), and Xu (Xu et al, “Understanding the Dose Regimen for Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma (MM) after Prior Proteasome Inhibitors (PIs) and Immunomodulatory Drugs (IMiDs): A Quantitative Pharmacologic Perspective”, December 3 2015, Blood, 126(23):4254 (pages 1-3 in pdf attached); hereinafter Xu).
Regarding instant claims 9, 10 and 16, the combined teachings of Chen and Garcia-Guerrero are discussed above.
However, the combined teachings of Chen and Garcia-Guerrero do not teach the combination of tinostamustine and daratumumab administered concurrently. Furthermore, the combined teachings of Chen and Garcia-Guerrero do not teach the combination of tinostamustine and daratumumab administered at a molar ratio of 1:1000 to 1000:1.
The deficiency is resolved by Mehrling and Xu.
Mehrling teaches treating ovarian cancer comprising administering tinostamustine or a combination thereof in a patient in need thereof (page 1, Abstract, page 20 column 2, line 41 – page 21, column 3, line 30). Mehrling also teaches that treatment with EDO-S101 demonstrated enhanced efficacy when in combination with carboplatin, paclitaxel and carboplatin+paclitaxel, compared to said treatments in the absence of EDO-S101 (page 26, column 13, lines 46-57). Mehrling further teaches a combination comprising tinostamustine and carboplatin, wherein the molar ratio of carboplatin to tinostamustine is typically from 1:2000 to 2000:1. The same molar ratio applies to the combination comprising tinostamustine and paclitaxel (page 24, column 10, line 54 – page 25, column 11, line 20). Furthermore, Mehrling teaches that EDO-S101 (tinostamustine) is administered at doses of 0.3-300 mg/m2 (page 22, column 6, lines 4-19). Mehrling also discloses that the combination comprising tinostamustine and carboplatin can be administered concurrently (page 21, column 3, lines 3-9 and 21-27).
Xu teaches that at 16mg/kg dose of daratumumab, there was no apparent relationship between the drug exposure and infusion related reactions, thrombocytopenia, anemia, neutropenia, or lymphopenia, and resulted in high overall response rates (page 2, last paragraph in §Results).
Regarding instant claim 9, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method of treating multiple myeloma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of tinostamustine in combination with a therapeutically effective amount of daratumumab, wherein the cancer is capable of expressing CD38 upon contacting tinostamustine as taught by the combined teachings of Chen and Garcia-Guerrero to further comprise that the combination of tinostamustine and Daratumumab are administered concurrently. This is obvious because, the combined teachings of Chen and Garcia-Guerrero teach a method of treating multiple myeloma comprising administering to a subject in need thereof an effective amount of tinostamustine, a potent HDAC inhibitor, and daratumumab, wherein the cancer expressed increased CD38 upon treatment with HDAC inhibitors, and Mehrling teaches a method of treating ovarian cancer comprising administering to a patient in need thereof a therapeutically effective amount of a combination comprising tinostamustine and carboplatin can be administered concurrently, wherein the combination treatment with EDO-S101 demonstrated enhanced efficacy when in combination with carboplatin, compared to treatments in the absence of EDO-S101. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating multiple myeloma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of tinostamustine in combination with a therapeutically effective amount of daratumumab, wherein tinostamustine and daratumumab is administered concurrently, and wherein the cancer is capable of expressing CD38 upon contacting tinostamustine.
Regarding instant claims 10 and 16, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method of treating multiple myeloma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of tinostamustine in combination with a therapeutically effective amount of daratumumab, wherein the cancer is capable of expressing CD38 upon contacting tinostamustine as taught by the combined teachings of Chen and Garcia-Guerrero to further comprise that the molar ratio of tinostamustine to daratumumab is 1:1000 to 1000:1 as taught by Mehrling and Xu. This is obvious because, the combined teachings of Chen and Garcia-Guerrero teach a method of treating multiple myeloma comprising administering to a subject in need thereof an effective amount of tinostamustine, a potent HDAC inhibitor, and daratumumab, wherein the cancer expressed increased CD38 upon treatment with HDAC inhibitors, Mehrling teaches that tinostamustine is administered at doses of 0.3-300 mg/m2, and Xu teaches that a 16mg/kg dose of daratumumab resulted in high overall response rates in patients. It is well known in the art that the molar mass of tinostamustine is 415.36 g/mol and the molar mass of daratumumab is 148,000 g/mol. Therefore, under the assumption of a standard person of 70kg body weight and 1.8m2 body surface area treated with 100 mg/m2 tinostamustine, the molar ratio calculation results in 57.2:1, which falls within the range recited in instant claims 10 and 16. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating multiple myeloma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of tinostamustine in combination with a therapeutically effective amount of daratumumab, wherein the cancer is capable of expressing CD38 upon contacting tinostamustine, and wherein the molar ratio of tinostamustine to daratumumab is 1:1000 to 1000:1.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Chen (US20110269706 A1, Priority to January 23, 2009, IDS entered on 5/15/2024; hereinafter Chen) and Garcia-Guerrero (Garcia-Guerrero et al, “Upregulation of CD38 expression on multiple myeloma cells by novel HDAC6 inhibitors is a class effect and augments the efficacy of daratumumab”, April 29 2020, Leukemia, 35:201-214; hereinafter Garcia-Guerrero), as applied to claim 1 above, and further in view of Nijhof (Nijhof et al, “Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab”, May 15 2015, Leukemia, 29:2039-2049; hereinafter Nijhof).
Regarding instant claim 11, the combined teachings of Chen and Garcia-Guerrero are discussed above.
However, the combined teachings of Chen and Garcia-Guerrero do not teach the method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of tinostamustine in combination with a therapeutically effective amount of daratumumab, wherein the cancer is capable of expressing CD38 upon contacting tinostamustine, wherein the expression of CD38 in the cancer is heterogeneous.
The deficiency is resolved by Nijhof.
Nijhof teaches that MM cells from patients were used to determine the impact of CD38 expression levels on daratumumab-mediated killing of MM cells. Nijhof discloses that as expected, all MM cells expressed CD38 antigen in these patients’ samples (n=144), but there was a marked heterogeneity in intensity of CD38 expression with median fluorescence intensity ranging from 19.99 to 2642 (median 401.3) (page 2041, right column, §Effect of CD38 expression on ADCC and CDC in primary MM cells; Figure 3).
Regarding instant claim 11, it would have been obvious for a person having ordinary skill in the art at the time of filing to modify the method of treating multiple myeloma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of tinostamustine in combination with a therapeutically effective amount of daratumumab, wherein the cancer is capable of expressing CD38 upon contacting tinostamustine as taught by the combined teachings of Chen and Garcia-Guerrero to further comprise that the expression of CD38 in cancer cells is heterogeneous. This is obvious because, the combined teachings of Chen and Garcia-Guerrero teach a method of treating multiple myeloma comprising administering to a subject in need thereof an effective amount of tinostamustine, a potent HDAC inhibitor, and daratumumab, wherein the cancer expressed increased CD38 upon treatment with HDAC inhibitors, and Nijhof teaches that all MM cells expressed CD38 antigen in the patients’ samples, but there was a marked heterogeneity in intensity of CD38 expression. Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant method of treating multiple myeloma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of tinostamustine in combination with a therapeutically effective amount of daratumumab, wherein the cancer is capable of expressing CD38 upon contacting tinostamustine, wherein the expression of CD38 in the cancer is heterogeneous.
Claims 18 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Chen (US20110269706 A1, Priority to January 23, 2009, IDS entered on 5/15/2024; hereinafter Chen) and Garcia-Guerrero (Garcia-Guerrero et al, “Upregulation of CD38 expression on multiple myeloma cells by novel HDAC6 inhibitors is a class effect and augments the efficacy of daratumumab”, April 29 2020, Leukemia, 35:201-214; hereinafter Garcia-Guerrero), as applied to claim 13 above, and further in view of Mehrling (US11,896,583 B2, Priority to June 13, 2017).
Regarding instant claims 18 and 19, the combined teachings of Chen and Garcia-Guerrero are discussed above.
However, the combined teachings of Chen and Garcia-Guerrero do not teach a kit comprising a pharmaceutical composition comprising the combination of tinostamustine and daratumumab and instructions.
The deficiency is resolved by Mehrling.
The teachings of Mehrling are discussed above. Mehrling further teaches a kit comprising the combination of tinostamustine and carboplatin, and instructions for treating a patient (page 21, column 3, lines 31-33).
Regarding instant claims 18 and 19, it would have been obvious for a person having ordinary skill in the art at the time of filing to take the kit comprising the pharmaceutical composition comprising the combination of tinostamustine and carboplatin and instructions as taught by Mehrling and substitute the pharmaceutical composition comprising tinostamustine and daratumumab as taught by the combined teachings of Chen and Garcia-Guerrero. This is obvious because, the combined teachings of Chen and Garcia-Guerrero teach a pharmaceutical composition comprising tinostamustine, a potent HDAC inhibitor, and daratumumab, and Mehrling teaches a kit comprising the combination of tinostamustine and carboplatin, and instructions for treating a patient. Additionally, absent a limiting definition for a “kit”, the broadest reasonable interpretation is any container comprising the instant pharmaceutical composition. Furthermore, printed instructions do not distinguish the claimed product (See MPEP 2112.01 (III)). Therefore, it is obvious to a skilled artisan with reasonable expectation of success to have been motivated to form the instant kit comprising the instant pharmaceutical composition comprising tinostamustine and daratumumab and instructions for treating a cancer in a patient.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jieun Ham whose telephone number is (571)272-7779. The examiner can normally be reached Monday - Friday 7-2.
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/J.H./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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