DETAILED ACTION
Claims 1-17 are pending, and the subject of the Office Action below.
Priority
The instant application, filed 8/4/2023 is a Continuation of 16839935, filed 4/3/2020, now abandoned. 16839935 is a Continuation of 15828939 , filed 12/01/2017, now abandoned filed April 3, 2020 is a continuation of 15828939, filed December 1, 2017 is a continuation of 14/856,217, filed September 16, 2015 is a continuation of 13/153,291, filed June 3, 2011, now abandoned and having 1 RCE-type filing therein, claims priority from provisional applications; 61/351130, filed June 3, 2010, 61/419,764, filed December 3, 2010, and 61/472,138, filed April 5, 2011.
Information Disclosure Statement
The Information Disclosure Statements (IDS) submitted on 3/27/2023 and 11/3/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the Information Disclosure Statements are being considered by the Examiner.
Claim Rejections - 35 USC § 102/103
The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 1 and 7-10 are is rejected under pre-AIA 35 U.S.C. 102(b) as anticipated by or, in the alternative, under pre-AIA 35 U.S.C. 103(a) as obvious over Friedberg et al. Blood 2010 (115) 2578-2585 published online on November 17, 2009 with evidence by Chen et al. Blood 2008 (111) 2230-2237; Kuglstatter et al. Protein Science 2011 (20) 428-436 and Davis et al. Nature 2010 (463) 88-92.
Claim 1 is directed towards a method for treating diffuse large B-cell lymphoma, activated B cell-like subtype (ABC-DLBCL), in an individual in need thereof, comprising: administering to the individual a therapeutically effective amount of an inhibitor of Bruton's tyrosine kinase (Btk).
Friedburg teaches the treatment of DLBCL with fostamatinib disodium. Fostamatinib is the prodrug of R406, he treats 21 patients with DBLCL; see Figure 2 page 2583. Friedburg does not “type” the DLBCL tumors, therefore it is unclear if they are ABC-DLBCL tumors.
Chen provides evidence that the DLBCL tumors of ABC type would be expected to respond to fostamatinib. Chen shows that fostamatinib/R406 kills LY10 cells. LY10 cells are ABC-DLBCL; page 2232 Figure 1.
Kuglstatter provides evidence to show that R406 is a Btk inhibitor, Figure 2 page 430.
The treatment of lymphoma, that appears to be of ABC type with fostamatinib (a Btk inhibitor) anticipates claim 1. At the time the invention was made, LY10 cells have not been fully characterized. Davis is provided to show that LY10 cells are ABC-DLBCL cells, and that they contain a CD79A ITAM mutation; see page 4, paragraph 3. This cell line clearly demonstrates that treatment of ABC-DLBCL with the mutations outlined in claims 7-10.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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, 7-10, and 13 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Yang et al. Leukimia 2008 (22) 1755-1766 with evidence from Hantschel et al. PNAS 2007 (104) 13283-13288 (in the IDS) and Davis et al. Nature 2010 (463) 88-92.
Claim 1 is directed towards a method for treating diffuse large B-cell lymphoma, activated B cell-like subtype (ABC-DLBCL), in an individual in need thereof, comprising: administering to the individual a therapeutically effective amount of an inhibitor of Bruton's tyrosine kinase (Btk). Claims 7-10 require certain mutations of CD79A. Claim 7, any mutation to CD79A; claim 8, to the ITAM region; claim 9, a splice donor site mutation; claim 10, the mutation deletes the ITAM module.
Yang teaches that dasatinib (a Btk inhibitor; see Hantschel, title) inhibits lymphoma cell lines LY1, LY7, LY8, and LY10; see page 1757, column 1, first paragraph. Dasatinib is found potent in LY10 cells. In general Yang teaches dasatinib should be used in vivo for the treatment of lymphoma in general.
Yang doesn’t explicitly teach the treatment of diffuse large B-cell lymphoma, activated B cell-like subtype (ABC-DLBCL), or lymphoma with the specific mutations outlined. However, one of ordinary skill in the art would reasonably expect that the compounds of Yang could be used for certain subtypes of lymphoma based on his findings because the activity of dasatinib towards LY10 was recognized as a used for ABC-DLBCL. Note that Yang does treat “lymphoma”, and specifically one would be motivated to treat “lymphoma” that has similar characteristics as the cell lines tested, and specifically one would be motivated to treat “lymphoma” with similar characteristics of the cell line, LY10, as this cell line showed the best response to dasatinib.
Therefore, a person of ordinary skill in the art would clearly recognize the use of dasatinib for the treatment of lymphomas, and specifically for lymphoma that is represented by the LY10 cell line (and the other cell lines in which positive results were seen).
At the time the invention was made, LY10 cells have not been fully characterized. Davis is provided to show that LY10 cells are ABC-DLBCL cells, and that they contain a CD79A ITAM mutation; see page 4, paragraph 3. This cell line clearly renders obvious the treatment of ABC-DLBCL with the mutations outlined in claims 7-10.
Claim Rejections - 35 USC § 103
Claims 1, 7-10, and 14-17 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Honigberg et al. WO 2008/121742 A2 published October 9, 2008 (in the IDS) and Greshock et al. Cancer Research 2010 (70) 3677-3686; with evidence from Davis et al. Nature 2010 (463) 88-92.
Claim 1 is directed towards a method for treating diffuse large B-cell lymphoma, activated B cell-like subtype (ABC-DLBCL), in an individual in need thereof, comprising: administering to the individual a therapeutically effective amount of an inhibitor of Bruton's tyrosine kinase (Btk). Claims 7-10 require certain mutations of CD79A. Claim 7, any mutation to CD79A; claim 8, to the ITAM region; claim 9, a splice donor site mutation; claim 10, the mutation deletes the ITAM module. Claim 14 requires the inhibitor is an irreversible inhibitor, claim 15 requires the inhibitor to form a covalent bond to a cysteine sidechain of the Btk. Claim 16 defines a genus of Btk inhibitors claimed:
PNG
media_image1.png
303
335
media_image1.png
Greyscale
Lastly, claim 17 requires a specific compound as the inhibitor:
PNG
media_image2.png
200
400
media_image2.png
Greyscale
Honigberg teaches that Compound 1, which is the same compound of instant claim 17. This compound inhibits Btk at 0.5 nM in a cellular proliferation assay and inhibits growth of DOHH2 (lymphoma) cells at 100 nM; see page 119, Table 2. This exact compound is also shown in Figure 1A to be highly effective in inhibiting lymphoma tumor cell growth in multiple lymphoma cell lines; DOHH2, DLCL2, LY10, WSU-NHL, Mino, DHL6. Figure 1A illustrates that the compound is most potent in LY10 cells. This compound irreversibly binds by forming a covalent bond to a cysteine sidechain of the Btk, see [00430] (as required by claims 14 and 15). This compound was used in vivo with 5E6 DOHH2 and DLCL2 cells to illustrate the treatment of lymphoma in a mouse, [00485]. In general Honigberg teaches potent compounds that are used in vivo for the treatment of lymphoma in general.
Honigberg doesn’t explicitly teach the treatment of diffuse large B-cell lymphoma, activated B cell-like subtype (ABC-DLBCL), or lymphoma with the specific mutations outlined. However, it is important to note that Honiberg does treat “lymphoma”, and specifically one would be motivated to treat “lymphoma” that has similar characteristics as the cell lines tested, and specifically one would be motivated to treat “lymphoma” with similar characteristics of the cell line, LY10, as this cell line showed the best response to Compound 1 (the same compound of the instant invention).
Greshock is brought in to provide motivation, background in the art, and to clarify what is implied in the teaching of Honigberg; also this reference provides understanding of what a “reasonable expectation of success” in cancer treatment looks like. Greshock teaches that preclinical cellular response profiles (similar to Honigberg showing excellent response in specific cell lines for lymphoma) have become the cornerstone in development of cancer therapeutics. Greshock shows that the response in a cell line is reasonably predictive to the response in vitro of cancers like that cell line. Greshock explains that the selection of patients with a tumor having a specific genotype maximizes the potential of development.
Therefore, a person of ordinary skill in the art would clearly recognize the use of Compound 1 for the treatment of lymphomas, and specifically for lymphoma that is represented by the LY10 cell line (and the other cell lines in which positive results were seen). This person having knowledge of the importance of patient stratification and genotyping cancer would be motivated to treat patients represented by LY10 cells. This person would also have a reasonable expectation of success in treating these patients as Greshock has shown that cellular models are predictive of in vitro results.
At the time the invention was made, LY10 cells have not been fully characterized. Davis is provided to show that LY10 cells are ABC-DLBCL cells, and that they contain a CD79A ITAM mutation; see page 4, paragraph 3. This cell line clearly renders obvious the treatment of ABC-DLBCL with the mutations outlined in claims 7-10.
Claim Rejections - 35 USC § 103
Claims 1-12 and 15-17 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Honigberg et al. WO 2008/121742 A2 published October 9, 2008 (in the IDS) and Greshock et al. Cancer Research 2010 (70) 3677-3686; in further view of Staudt et al. US 2007/0105136 A1 published May 10, 2007, with evidence from Davis et al. Nature 2010 (463) 88-92.
Claim 1 is directed towards a method for treating diffuse large B-cell lymphoma, activated B cell-like subtype (ABC-DLBCL), in an individual in need thereof, comprising: administering to the individual a therapeutically effective amount of an inhibitor of Bruton's tyrosine kinase (Btk). Claim 2 requires that the individual be diagnosed, by determining the gene sequence of one or more biomarkers in a plurality of lymphoid cells isolated from the large B-cell lymphoma. Claims 3-12 are directed towards specific mutations in the lymphoma to be treated, thereby further refining the patient population. Claim 14 requires the inhibitor is an irreversible inhibitor, claim 15 requires the inhibitor to form a covalent bond to a cysteine sidechain of the Btk. Claim 16 defines a genus of Btk inhibitors claimed:
PNG
media_image1.png
303
335
media_image1.png
Greyscale
Lastly, claim 17 requires a specific compound as the inhibitor:
PNG
media_image2.png
200
400
media_image2.png
Greyscale
Honigberg teaches that Compound 1, which is the same compound of instant claim 17. This compound inhibits Btk at 0.5 nM in a cellular proliferation assay and inhibits growth of DOHH2 (lymphoma) cells at 100 nM; see page 119, Table 2. This exact compound is also shown in Figure 1A to be highly effective in inhibiting lymphoma tumor cell growth in multiple lymphoma cell lines; DOHH2, DLCL2, LY10, WSU-NHL, Mino, DHL6. Figure 1A illustrates that the compound is most potent in LY10 cells. This compound irreversibly binds by forming a covalent bond to a cysteine sidechain of the Btk, see [00430] (as required by claims 14 and 15). This compound was used in vivo with 5E6 DOHH2 and DLCL2 cells to illustrate the treatment of lymphoma in a mouse, [00485]. In general Honigberg teaches potent compounds, that are used in vivo for the treatment of lymphoma in general.
Honigberg doesn’t explicitly teach the treatment of diffuse large B-cell lymphoma, activated B cell-like subtype (ABC-DLBCL), or lymphoma with the specific mutations outlined. However, it is important to note that Honiberg does treat “lymphoma”, and specifically one would be motivated to treat “lymphoma” that has similar characteristics as the cell lines tested, and specifically one would be motivated to treat “lymphoma” with similar characteristics of the cell line, LY10, as this cell line showed the best response to Compound 1 (the same compound of the instant invention).
Greshock is brought in to provide motivation, background in the art, and to clarify what is implied in the teaching of Honigberg; also this reference provides understanding of what a “reasonable expectation of success” in cancer treatment looks like. Greshock teaches that preclinical cellular response profiles (similar to Honigberg showing excellent response in specific cell lines for lymphoma) have become the cornerstone in development of cancer therapeutics. Greshock shows that the response in a cell line is reasonably predictive to the response in vitro of cancers like that cell line. Greshock explains that the selection of patients with a tumor having a specific genotype maximizes the potential of development.
Therefore, a person of ordinary skill in the art would clearly recognize the use of Compound 1 for the treatment of lymphomas, and specifically for lymphoma that is represented by the LY10 cell line (and the other cell lines in which positive results were seen).
At the time the invention was made, LY10 cells have not been fully characterized. Davis is provided to show that LY10 cells are ABC-DLBCL cells, and that they contain a CD79A ITAM mutation; see page 4, paragraph 3. This cell line clearly renders obvious the treatment of ABC-DLBCL with the mutations outlined in claims 7-10.
Staudt teaches the method of diagnosing ABC-DLBCL genes as required by claim 2 using a microarray; see Example 1 page 17.
A person of ordinary skill in the art, after seeing the cellular data of Honigberg would then profile the lymphoma cells using the methods of Staudt in order to improve the response rate of the drug. One would do this in order to predict what patients would best match the treatment with Compound 1. Thereby one would treat patients that have similar "lymphomas" as that seen in the cellular genotype of the cancer cells treated by Honigberg. Without the ability to run experiments, here at the Patent Office, the Examiner is unable to access the inherent disclosure of the Honigberg reference. On the face, it appears that the mutations described in claims 3-12 would be found by simple analysis of the cell lines previously tested by Honigberg. As such all these “mutations” would fall under the treatment of "lymphomas” similar to that already known to be treatable by Honigberg. Therefore the invention as a whole is found prima facie obvious at the time it was made.
Conclusion
In view of the rejections to the pending claims set forth above, no claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL J SCHMITT whose telephone number is (571)270-7047. The examiner can normally be reached on M-F 8-6 MidDay Flex.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Lundgren can be reached on 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MICHAEL SCHMITT/
Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629