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 .
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 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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/19/2026 has been entered.
Claims 106 and 116 are amended and claims 1-105, 110-111, 113-114, 117-118, and 120-121 are cancelled. Claims 106-109, 112, 115-116, 119, and 122-125 are currently pending and are examined on the merits herein.
Priority
The instant application, filed 12/22/2022, is a continuation of US application 16/633,132, filed 01/22/2020, which is a 371 filing of PCT/EP2018/070856, filed 08/01/2018, and claims foreign priority to EP17184277.6, filed 08/01/2017.
Withdrawn Objections and Rejections
In the office action of 11/202026,
Claims 106-109, 112, 115-116, 119, and 122-125 were rejected under 35 USC 103 over Weisberg, WO’889, and WO'657; and claims 110-111 and 117-118 were rejected under 35 USC 103 over Weisberg, WO’889, WO'657, and Larrosa-Garcia. Applicant’s amendment to independent claims 106 and 116 to require that the FLT3 kinase inhibitor be crenolanib or quizartinib and that the kinase inhibitor and targeting agent act synergistically has overcome the rejections and the rejections are withdrawn. Additionally, the cancellation of claims 110-111 and 117-118 has rendered the rejections of these claims moot and the rejections are withdrawn.
The rejections in the instant office action are new as necessitated by applicant’s amendment to the claims.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
In the specification amendment of 12/22/2022, the incorporation by reference paragraph recites the XML sequence listing file size in kilobytes rather than the required bytes. See 1.a.iii and 1.b.iii above. Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 112 and 119 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 112 and 119 depend on claims 106 and 116, respectively, and recite the limitation that the FLT3 kinase inhibitor is midostaurin. Claims 106 and 116; however, have been amended to limit the FLT3 kinase inhibitor to crenolanib or quizartinib. As such, the limitations of claims 112 and 119 are broader in scope than the claims upon which they depend and do not include all of the limitations of the claims upon which they depend.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 106-109, 112, 115-116, 119, and 122-125 are rejected under 35 U.S.C. 103 as being unpatentable over Weisberg, E. et al (2011) Reversible resistance induced by FLT3 inhibition: A novel Resistance Mechanism in mutant FLT3-expressing cells PLos ONE 6(9) e25351; 1-12 in view of WO 2017/053889 A2 (Devine, S., et al) 30 March 2017, Larrosa-Garcia, M. and M.R. Baer (2017) FLT3 inhibitors in acute myeloid leukemia: Current status and future directions Mol Cancer Ther 16(6); 991-1001, published June 2017, and WO 2015/142675 A2 (Loew, A., et al) 24 SEPT 2015.
Weisberg teaches that over-expression of FLT3 protein in response to kinase inhibitors may be part of a novel mechanism that could contribute to clinical resistance (abstract, Results and Conclusions). Weisberg teaches that a constitutively activated, mutated version of the class III receptor tyrosine kinase, FLT3, is expressed in approximately 30% of acute myeloid leukemia (AML) patients and a subset of ALL patients. The most prevalent form of mutant FLT3, present in approximately 20-25% of AML patients, occurs as internal tandem duplications (ITD) within the juxtamembrane domain (page 1, left column, paragraph 1). Thus, mutant FLT3 represents an attractive target for the therapy of AML. Several FLT3 inhibitors, including the N-indolocarbazole PKC412, also known as midostaurin, have shown sufficient efficacy and safety profiles to warrant further studies in combination with standard therapies in advanced clinical trials. However, inhibitors of FLT3 have generally elicited partial and transient clinical responses in early trials. The observed suboptimal clinical responses, coupled with detection of drug-resistant leukemic blast cells in FLT3 inhibitor-treated AML patients, have made understanding clinical resistance to FLT3 inhibitors a priority (page 1, right column, paragraph 1).
Weisberg teaches that in a phase II trial of the FLT3 inhibitor lestaurtinib (CEP701) in patients with both mutated and wild-type FLT3-expressing AML, most of the patients in which blast surface FLT3 expression was able to be measured showed an elevation in blast surface FLT3 expression while treatment with lestaurtinib ensued. Authors of the study speculated that this up-regulation of FLT3 receptor expression might have contributed to the limited clinical benefit and, therefore, might represent a potential mechanism of resistance (page 2, left column, paragraph 1).
Weisberg used two structurally distinct FLT3 kinase inhibitors, PKC412 and the novel type II ATP competitive inhibitor HG-7-85-01, to generate resistant cell lines using the human AML cell line MOLM-13 which expresses FLT3-ITD. The cell lines obtained were cross-resistant and, in both cases, resistance was associated with a striking over-expression of the mutant FLT receptor, a finding reflective of the previously observed up-regulation of surface FLT3 receptor expression in FLT3 inhibitor-treated patients (page 2, left column, paragraph 3; page 2, left column, paragraph 5). Weisberg found that MOLM13 cells readily developed cross-resistance when exposed to either midostaurin or HG-7-85-01 and resistance in both lines was associated with dramatically elevated levels of cell surface FLT3. The increase in FLT3-ITD expression was at least in part due to reduced turnover of the receptor with prolonged half-life. Importantly, the drug-resistant phenotype could be rapidly reversed upon withdrawal of either inhibitor (abstract, results and conclusions).
Weisberg teaches that the findings suggest that there may be benefits to the use of combination therapy as a way to enhance the efficacy of FLT3 inhibitors and override drug resistance. The data presented points towards the potential use of FLT3 antibodies or other FLT3 target-specific therapies as a way to override drug-resistance (page 9, right column, paragraph 3).
The teachings of Weisberg differ from the instantly claimed invention in that Weisberg does not disclose that the FLT3 target-specific therapy is an immune cell expressing a CAR that binds to the extracellular domain of FLT3 or that the FLT3 kinase inhibitor is crenolanib or quizartinib administered at least once or multiple times after the FLT3 targeting CAR.
WO’889 teaches that despite a broad understanding of the molecular and genetic complexities of AML, only allogeneic hematopoietic stem cell transplant (HSCT) provides significant improvements in the clinical outcome of patients. However, elderly patients may not be eligible for HSCT and this approach is also associated with complications that can result in significant morbidity and mortality, such as GVHD. Moreover, patients with a FLT3 internal tandem duplication (ITD) mutation have an especially adverse prognosis and high probability of relapse (pages 1-2, [0005]).
WO’889 teaches that CAR engineered T cells graft the specificity of the monoclonal antibody with specific antitumor activity of cytotoxic T lymphocytes (CTL) to acquire the activity of recognizing tumor surfaced antigen and killing specific malignant tumors once the genetically modified T cell is activated. WO’889 teaches that FLT3 is a highly expressed surface protein in leukemia, especially in AML (page 2, [0007]). WO’889 discloses a CAR comprising the antigen binding domain of a FLT3 antibody that binds FLT3 (page 4, [0011]; page 38, [0129]). As WO’889 teaches that the antibody in CARs recognize tumor surface antigens and that the antibody binds FLT3, an ordinarily skilled artisan would reasonably envision that the CAR binds to the extracellular domain of FLT3 which is the part of the antigen that is exposed on the surface of the tumor cells.
WO’889 further teaches compositions comprising the CAR T cells (page 6, [0025]). WO’889 teaches that a “composition” intends a combination of the active agent and carriers as well as adjuvants (page 20, [0073]).
WO’889 studied the use of the FLT3-specific T cells to kill primary AML cells in studies using the MOLM-13 cell line and teaches that the FLT3 CAR T cells robustly lysed the MOLM-13 cells tested (page 69, [0229]; Figure 3).
Larrosa-Garcia teaches that FLT3 is involved in regulating survival, proliferation, and differentiation of hematopoietic stem/progenitor cells and is expressed on AML cells in most patients. Patients with AML with FLT3-ITD mutations have a high relapse rate and short relapse-free and overall survival after chemotherapy and after transplant. A number of inhibitors of FLT3 signaling have been identified and are in clinical trials, both alone and with chemotherapy, with the goal of improving clinical outcomes in patients with AML and FLT3 mutations (abstract).
Larrosa-Garcia teaches that the primary approach in inhibiting FLT3 signaling to produce cytotoxicity and clinical response has been identification and testing of small molecule inhibitors of FLT3 signaling and that some work has also focused on developing internalizing fully human antagonistic antibodies directed against FLT3 (page 2, paragraph 3). A number of FLT3 inhibitors have been studied and are classified into first- and second- generation based on their specificity for FLT3 and into type I and type II based on their mechanism of interaction with FLT3 (page 3, paragraph 4). Larrosa-Garcia provides a summary of FLT3 inhibitors in clinical trial for AML in Table 1.
As shown in table 1, type I inhibitors include sunitinib, midostaurin, lestaurtinib, KW-2449, crenolanib, and gilteritinib and type II inhibitors include sorafenib, ponatinib, tandutinib, and quizatinib.
Larrosa also provides the IC50 of the inhibitors for ITD, which demonstrates that they are all active against the mutation, as well as other targets for which the inhibitors are active.
WO’675 teaches compositions and methods for treating diseases associated with expression of cancer associated antigens including the administration of genetically modified T cells that express a CAR (abstract). WO’675 teaches immune effector cells, such as T cells or NK cells, that are engineered to express a FLT3 CAR for the treatment of cancer cells that express FLT3, such as AML (page 183, [00720]). WO’675 further teaches that in some embodiments, the CAR is administered in combination with an agent that increases the efficacy of the immune effector cell, for example a kinase inhibitor (page 20, [0070]). A CAR-expressing cell and the at least one additional therapeutic agent can be administered simultaneously, in the same or separate compositions, or sequentially. For sequential administration, the CAR-expressing cell can be administered first, and the additional agent can be administered second, or the order of administration can be reversed (pages 206-207, [00869]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to have modified the method disclosed by Weisberg by substituting the FLT3 targeting antibodies and agents suggested by Weisberg with the FLT3 targeting CAR T cells of WO’889, particularly in subjects in which blast FLT3 expression is elevated during treatment with FLT3 KIs as taught by Weisberg. It would have further been obvious to substitute the FLT3 KIs with the kinase inhibitors disclosed by Larrosa-Garcia, including crenolanib or quizartinib and to administer the kinase inhibitor in the same or separate compositions and sequentially with either the CAR expressing cell before or after the kinase inhibitor as disclosed by WO’675. An ordinarily skilled artisan would have reasonably expected that the combination of the FLT3 kinase inhibitor and the FLT3 CAR T cells would act synergistically based on the teachings of Weisberg and WO’675.
An ordinarily skilled artisan would have been motivated to substitute the FLT3 targeting CAR T cells of WO’889 in place of the FLT3 targeting antibodies and agents, particularly in subjects in which blast FLT3 expression is elevated during treatment with FLT3 KIs as taught by Weisberg, as WO’889 demonstrates that FLT3 CAR T cells are able to robustly lyse AML cells by combining the specificity of an antibody with the antitumor activity of a T cell. An ordinarily skilled artisan would have had a reasonable expectation of success as Weisberg demonstrates patient populations in which FLT3 KIs increase the surface expression of FLT3 on FLT3-ITD AML cells and, based on this increased expression, suggests the use of FLT3 targeting agents, agents which encompass the FLT3 targeting CAR of WO’889. Additionally, WO’889 demonstrates that the FLT3 targeting CAR T cells were able to robustly lyse the MOLM-13 AML cell line, which is one of the same cell line used in the studies performed by Weisberg and demonstrated to have increased FLT3 expression upon FLT3 KI treatment.
It would have further been obvious to an ordinarily skilled artisan to substitute the FLT3 KIs of Weisberg with crenolanib or quizartinib as Larrosa-Garcia demonstrates that they were known FLT3 kinase inhibitors that were being tested in clinical trial for the treatment of AML. One of ordinary skill in the art would have had a reasonable expectation of success because Larrosa-Garcia demonstrates that, like the midostaurin, lestaurtinib and HG-7-85-01 disclosed by Weisberg, crenolanib and quizartinib are both active in targeting FLT3-ITD. Weisberg also demonstrates that overexpression of FLT3 was observed in two cell lines in response to structurally unrelated FLT3 inhibitors, suggesting that FLT3 kinase inhibitors would be expected to result in such increase, regardless of their structure. Additionally, all of midostaurin, lestaurtinib, and crenolanib are type I inhibitors, indicating that they interact with FLT3 in the same way. Furthermore, the table of Larrosa-Garcia demonstrates that all of the inhibitors target FLT3 ITD, but that the other targets differ among the inhibitors, suggesting that the results observed are a function of targeting FLT3, not one of the other targets. This conclusion of obviousness is further supported by KSR (E) obvious to try. See MPEP 2143. In this case, the prior art teaches the use of FLT3 targeting agents in combination with FLT3 KIs to treat cancer. The prior art also recognized a finite number of FLT3 KIs. An ordinarily skilled artisan would have been able to pursue these known FLT3 KIs with the reasonable expectation that targeting FLT3 in FLT3-ITD mutated AML with KIs would result in the increased surface expression of FLT3 allowing for targeting with FLT3 targeting agents, such as the CAR T cells of WO’889.
It would have been obvious to an ordinarily skilled artisan to administer the kinase inhibitor at least once in the same or separate compositions, or sequentially, as WO’675 demonstrates that these methods of administration were known in the art for the treatment of cancer using CARs and additional agents such as kinase inhibitors. Additionally, Weisberg motivates administration of the FLT3 kinase inhibitor either at the same time or following CAR administration by teaching that increases in FLT3-ITD expression was at least in part due to reduced turnover of the receptor with prolonged half-life but that such phenotype could be rapidly reversed upon withdrawal of either midostaurin or HG-7-85-01 inhibitors. As the CARs of WO’889 target FLT3, an ordinarily skilled artisan would be motivated to maintain or initiate increased levels of FLT3 for targeting through concurrent or post administration of the FLT3 KI. An ordinarily skilled artisan would have had a reasonable expectation of success as WO’675 teaches methods of co-administering CARs and agents that increase the efficacy of CARs, such as kinase inhibitors, which are the same type of therapeutics taught by Weisberg and WO’889.
An ordinarily skilled artisan would have reasonably expected that the combination of the FLT3 kinase inhibitor and the FLT3 CAR T cells would act synergistically based on the teachings of Weisberg and WO’675. Specifically, Weisberg teaches that the use of FLT3 antibodies or other FLT3 target specific therapies could be a way to override drug resistance in FLT3 KIs, teachings which suggest that FLT3 targeting therapies would improve performance of FLT3 KIs, particularly in patient populations in which FLT3 KIs result in elevated blast surface FLT3 expression during treatment. WO’675 also teaches that kinase inhibitors can increase the efficacy of immune effector cells. Combined increased in efficacy of both FLT3 KIs and immune effector cells is indicative of synergistic results.
Furthermore, the teachings of Weisberg suggests the administration of FLT3 targeting antibodies and agents in patients in which FLT3 KIs result in FLT3 overexpression and WO’889 teaches CAR T cells that target FLT3. The substitution of the CAR T cells of WO’889 in place of the FLT3 antibodies and agents in the method disclosed by Weisberg would naturally result in synergistic effects due to the increased blast surface FLT3 expression as evidenced by the instant disclosure. For instance, Weisberg demonstrates that FLT3 KIs including midostaurin, HG-7-85-01, and lestaurtinib are associated with increased cell surface levels of FLT3 in MOLM13 cell lines and, based on this expression, suggests combining the inhibitors with anti-FLT3 targeting therapies. The instant disclosure demonstrates that increased FLT3 expression, including from the administration of midostaurin, in combination with FLT3 targeting CAR T cells, results in synergistic therapeutic outcomes.
MPEP 2145 II. states “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” The MPEP section further states “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”
Response to Arguments
Applicant’s arguments filed 05/19/2026 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
With regards to the rejections under 35 USC 103, applicant argues that one of ordinary skill in the art would not have substituted the FLT3 KIs disclosed by Weisberg, WO’889, and WO’675 with the KIs of Larrosa-Garcia.
Specifically, applicant argues that one of ordinary skill in the art would not have had a reasonable expectation that treatment with crenolanib or quizartinib would necessarily lead to upregulation of FLT3 merely because such an effect had been observed with midostaurin and/or HG-7-85-01. Applicant argues that the inhibitors were materially different in their kinase selectivity profiles and binding modes. Applicant argues that crenolanib is a type I inhibitor while quizartinib and HG-7-85-01 are associated with type II binding behaviors, i.e. binding to different conformational states of the kinase. Applicant argues that the compounds are not interchangeable.
This argument is not persuasive.
It is first noted that, as discussed in detail in the rejection, Weisberg also teaches that in clinical trials, patients treated with the FLT3 kinase inhibitor lestaurtinib showed elevated blast surface expression of FLT3 while treatment ensued. Weisberg then demonstrates similar increases in expression of the FLT3 receptor when two structurally different FLT3 kinase inhibitors, midostaurin and HG-7-85-01, were used, indicating that even structurally different FLT3 kinase inhibitors would be reasonably expected to upregulate the expression of FLT3. In total, the teachings of Weisberg demonstrate that all of lestaurtinib, midostaurin, and HG-7-85-01 result in an upregulation of FLT3 expression during treatment of AML.
With regards to applicant’s arguments that the inhibitors are materially different in their kinase selectivity profiles, it is considered that the combined teachings of the prior art suggest that the increase in FLT3 expression is a result of FLT3-ITD targeting, not the other targets that could be inhibited by the KI. For instance, Larrosa-Garcia provides a table of the FLT3 inhibitors that were in clinical trial for the treatment of AML. From the table, it is clear that midostaurin and lestaurtinib, both of which are taught by Weisberg to increase FLT3 expression during use, inhibit ITD. While each of the KI also inhibit other targets, it is not apparent that these targets overlap, suggesting that the related outcome is associated with the inhibition of FLT3-ITD, not one of the other targets.
With regards to applicant’s arguments concerning the type of inhibitor and the conformational state of the kinase that is bound, the table in Larrosa-Garcia identifies all of midostaurin, lestaurtinib, and crenolanib as type I inhibitors, indicating that they bind to the same conformational state of the kinase. Furthermore, according to applicant’s response, HG-7-85-01 and quizartinib are associated with type II binding behaviors, indicating that they bind to the same conformational state of the kinase. As such, even if the expression was related to the conformational state of the kinase that is bound, an ordinarily skilled artisan would still have had a reasonable expectation of success.
Based on these teachings of the combined prior art, one of ordinary skill in the art would have reasonably expected that a FLT3 kinase inhibitor would increase expression of FLT3, particularly in the patient population disclosed by Weisberg. Applicant does not provide any evidence to demonstrate that this is not predictable or to support the speculation that the inhibitors are not interchangeable.
Applicant further argues that any increase in FLT3 abundance at the transcript, total protein, or cell-surface level would have been regarded as a secondary cellular response, not a primary or intended pharmacological effect of FLT3 kinase inhibition. Applicant argues that the primary art recognized action of these compounds was suppression of the FLT3 kinase signaling and downstream proliferation pathways in FLT3-driven AML. Applicant argues that the prior art does not provide guidance that inhibition of FLT3 kinase activity, irrespective of inhibitor chemotype, would trigger compensatory receptor accumulation, altered trafficking, or increased surface display.
These arguments are not persuasive.
Even if the increase in FLT3 expression was a secondary response, not the intended or primary effect of FLT3 kinase inhibition, the prior art recognized such a secondary response in patients treated with FLT3 kinase inhibitors and in models studying the effects of FLT3 kinase inhibitors. For instance, as discussed in detail in the rejection, Weisberg teaches that, in clinical trials, the FLT3 inhibitor lestaurtinib was found to increase blast surface FLT3 expression while treatment ensued. Weisberg demonstrates similar increases in FLT expression using structurally distinct inhibitors, midostaurin and HG-7-85-01. Weisberg directly teaches that the data points towards the potential use of anti-FLT3 antibodies or other FLT3 target specific therapies as a means to override drug resistance in FLT3 KI treated AML. These teachings demonstrate that, even if increased expression was not the intended outcome, it was still an art recognized outcome as was the potential for combination with FLT3 targeting therapies.
Applicant further argues that, even if Weisberg demonstrates upregulation for midostaurin and HG-7-85-01, an ordinarily skilled artisan would attribute the observation as being compound specific or context-specific, rather than a universal rule. In particular, applicant argues that, because the inhibitors have broader kinase activity than crenolanib or quizartinib, any observed increase could have been understood as arising from indirect perturbation of signal networks, transcriptional feedback loops, receptor maturation pathways, or intracellular trafficking machinery, rather than from FLT3 inhibition.
This argument is not persuasive.
It is first noted that, while Weisberg does not demonstrate the effect as a “universal rule” conclusive proof of efficacy is not required to establish obviousness for which the standard is a reasonable expectation of success. See MPEP 2143.02 I.
As discussed in detail above, Weisberg demonstrates that increased expression of FLT3 was observed using three structurally distinct inhibitors, namely lestaurtinib, midostaurin, and HG-7-85-01. For at least lestaurtinib and midostaurin, the table in Larrosa-Garcia demonstrates that, while the inhibitors do have broader kinase activity, the broader targets do not appear to overlap, suggesting that the results observed are due to FLT3 inhibition.
Applicant further argues that the claims have been amended to specify that the FLT3 kinase inhibitor and the FLT3 targeting agent act synergistically. Applicant argues that the art does not teach that the combination may be synergistic, in part because of the cross-resistance reported and the broad inhibitory activity of TKIs. Applicant argues that the synergy observed is therefore surprising and that the claims reflect an unexpected result.
With regards to applicant’s arguments concerning cross-resistance, while Weisberg teaches the development of cross-resistance, Weisberg does not teach that the cross-resistance is to FLT3 targeting agents. Rather, the cross resistance discussed pertains to alternative FLT3 kinase inhibitors and chemotherapy. These teachings do not suggest that one of ordinary skill in the art would not expect synergistic results using CAR T cells targeting FLT3.
Applicant’s arguments concerning the broad inhibitory activities of FLT3 KI were also not persuasive for the reasons discussed in detail above.
As discussed in detail in the rejection of the instant office action, one of ordinary skill in the art would have reasonably expected that the combination of the FLT3 kinase inhibitor and the FLT3 targeting agent would act synergistically in the treatment of FLT3-ITD mutation positive AML based on the teachings of the combination of applied references. Specifically, Weisberg teaches that the use of FLT3 antibodies or other FLT3 target specific therapies could be a way to override drug resistance in FLT3 KIs, indicating an increase in FLT3 KI efficacy, particularly in patients with increased blast FLT3 surface expression resulting from FLT3 KI treatment. WO’675 teaches that kinase inhibitors can increase the efficacy of immune effector cells. Teachings which, together suggest synergy. Furthermore, as discussed in detail in the rejection, the combination of applied prior art suggests the combination of FLT3 kinase inhibitors that increase FLT3 surface expression, including FLT3 KIs such as midostaurin, with anti-FLT3 targeting agents, which encompasses the CAR T cells of WO’889. The combination of FLT3 KIs that increase surface expression of FLT3 with the CAR T cells of WO’889 would naturally result in synergistic outcomes as evidenced by the instant disclosure. For instance, the instant disclosure demonstrates that midostaurin, which was also studied by Weisberg, synergized with CAR T cell therapy.
It is also noted that MPEP 716.02 states that “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.” The MPEP section also states that “A difference of degree is not as persuasive as a difference in kind – i.e., if the range produces ‘"a new property dissimilar to the known property,’" rather than producing a predictable result but to an unexpected extent.”
Additionally, even if the result claimed was identified as being reflective of an unexpected result, which it is not, the independent claim is not commensurate in scope with the synergistic results provided in the specification. See MPEP 716.02 (d).
For instance, the independent claim encompasses the treatment of any type of cancer while the examples demonstrate the claimed result only in an AML cell line that has an ITD mutation in the FLT3 gene (pages 79-80).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AUDREY L BUTTICE whose telephone number is (571)270-5049. The examiner can normally be reached M-Th 8:00-4:00.
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, Joanne Hama can be reached on 571-272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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