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 .
DETAILED ACTION
This application is a 371 of PCT/US2023/027665.
The amendment filed on December 31, 2024 has been entered.
Status of Claims
Claims 1-3, 6, 9, 12, 15, 18-20, 22, 24-26, 28, 30-33, 35-37, 39, 42, 46, 54-56, 58-59, and 62 are pending.
Claims 1-3, 6, 9, 12, 15, 18-20, 22, 24-26, 28, 30-33, 35-37, 39, 42, 46, 54-56, 58-59, and 62 are under examination.
Claim for Domestic Priority
Applicants' claim for domestic priority under 35 USC 119(e) to US provisional application 63/389,327, filed on 07/14/2022, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on December 31, 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see pages 35, 85, and 94). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 24-25 objected to due to the recitation of an internal period after “E-coli” in line 2 of claims 24-25. Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See MPEP 608.01(m).
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 2 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “small molecule” in claim 2 is a relative term which renders the claim indefinite. The term “small molecule” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear as to what inhibitor is considered as a “small molecule”. A perusal of the specification did not provide a clear definition for the above limitation. Without a clear definition in terms of numerical value, those skilled in the art would be unable to ascertain an inhibitor that is a small molecule. Appropriate correction is required.
For examination purpose, the term has been broadly interpreted as any molecule.
Claim 20 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 20 recites the broad recitation “at least 80%..” and “at least 99%”, which is the narrower statement of the range/limitation. The limitation “at least 80%” is equivalent to a range of “80%-100%” and the limitation “at least…99%” is equivalent to a range of “99%-100%”. Therefore, the claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Appropriate correction is required.
Claim 24 and claim 25 depending therefrom are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “hypersensitivity” in claim 24 is a relative term which renders the claim indefinite. The term “hypersensitivity” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear as to how much sensitivity is considered as “hypersensitivity”. A perusal of the specification did not provide a clear definition for the above limitation. Without a clear definition in terms of numerical value, those skilled in the art would be unable to ascertain what levels of sensitivity is “hypersensitivity”. Appropriate correction is required.
Claim 28 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 28 recites the broad recitation “less than 6% aggregation” and “less than 1% aggregation”, which is the narrower statement of the range/limitation. The limitation “less than 6%” is equivalent to a range of “0-6%” and the limitation “less than 1%” is equivalent to a range of “0-1%”. Therefore, the claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Appropriate correction is required.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 6, 9, 12, 15, 18-20, 22, 24-26, 28, 30-33, 35-37, 39, 42, 46, 54-56, 58-59, and 62 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
It is noted that MPEP 2111.01 states that ''[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow.'' In the instant case, the claims encompass a method of treating a genus of cancers by administering a genus of asparaginase and genus of inhibitors of BCL-XL, BCL-2, both BCL-XL and BCL-2, mTOR, CD20, and BTK.
MPEP 2163 I. states that to “satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.
MPEP 2163. II.A.3.(a) sates that “Possession may be shown in many ways. For example, possession may be shown by describing an actual reduction to practice of the claimed invention. Possession may also be shown by a clear depiction of the invention in detailed drawings or in structural chemical formulas which permit a person skilled in the art to clearly recognize that inventor had possession of the claimed invention. An adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics so long as a person skilled in the art would recognize that the inventor had possession of the claimed invention.
According to MPEP 2163.II.A.3.(a).ii), “Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus…Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’"
The recitations of “cancer..ALL, lymphoblastic lymphoma (LBL), acute myeloid leukemia (AML) colorectal cancer (CRC), breast cancer, pancreatic cancer, glioblastoma, lung cancer, small cell lung cancer (SCLC), ovarian cancer, sarcoma, and gastric cancer”, “asparaginase”, and inhibitors of “BCL-XL, BCL-2, both BCL-XL and BCL-2, mTOR, CD20, and BTK” fail to provide a sufficient description of a method of treating a genus of cancer by administering of asparaginase and inhibitors as it merely describes the functional features of the genus without providing any definition of the structural features of the species within the genus. The specification does not specifically define any of the species that fall within the genus. The specification does not define any structural features commonly possessed by members of the genus that distinguish them from others. One skilled in the art therefore cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus.
The prior art discloses treating some cancer using E. coli or Erwinia chrysanthemi L-asparaginase and one or more of the inhibitors recited in claims 6, 9, 12, 15, and 18, see Aivado (US 2017/0114098 - PTO-892), Emadi (WO 2020/132184 – form PTO-1449). However, Brigitha (Hypersensitivity to Pegylated E.coli asparaginase as first-line treatment in contemporary paediatric acute lymphoblastic leukaemia protocols: a meta-analysis of the Ponte di Legno Toxicity working group. Eur J Cancer. 2022 Feb;162:65-75. Epub 2021 Dec 23 – form PTO-892) discloses that administration of E. coli asparaginase to treat ALL results in hypersensitivity to said asparaginase (abstract). Therefore, neither the prior art nor the instant specification provide guidance on a method of treating any cancer or the cancers recited in claims 35-37 by administering any asparaginase and any inhibitors of BCL-XL, BCL-2, both BCL-XL and BCL-2, mTOR, CD20, and BTK.
The specification is limited to an in vitro assay detecting cytotoxicity of a few cancer cell lines by combining (a) long acting Erwinia chrysanthemi L-asparaginase (JZP-458) and (b) A-1331852 (BCL-XL inhibitor), Venetoclax (BCL-2 inhibitor), Navitoclax (BCL-2/BCL-XL inhibitor), CB-839 (glutaminase inhibitor) or A-1155463 (BCL-XL inhibitor) in vitro (see Figures 1-6). While MPEP 2163 acknowledges that in certain situations “one species adequately supports a genus,” it also acknowledges that “[f]or inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.” In view of the widely variant species encompassed by the genus, the example described above is not enough and does not constitute a representative number of species to describe the whole genus. Therefore, the specification fails to describe a representative species of the claimed genus.
Further, the claimed invention requires a defined set of asparaginases and inhibitors to treat a genus of cancers. Although the specification discloses exemplary asparaginases and inhibitors, a “laundry list” disclosure of every possible moiety does not necessarily constitute a written description of every species in a genus because it would not “reasonably lead” those skilled in the art to any particular species, see Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996) or MPEP 2163. While the asparaginase and inhibitors were known in the art, this knowledge alone would not allow one level of skill in the art to immediately envisage the claimed method of treating any cancer or the cancers recited in claims 35-36. Therefore, the level of skill and knowledge in the art is such that one of ordinary skill would not be able to identify without further testing which combination of asparaginase and inhibitors to use in the claimed method.
Regarding claims 20 and 22, one of skill in the art could identify variants having at least 80%-95% sequence identity to SEQ ID NO:1. However, there is no teaching regarding which 5%-20% of the amino acids of SEQ ID NO:1 can vary and result in a polypeptide having asparaginase activity and having efficacy in treating the claimed genus of cancers.
Fransceus (J Ind Microbiol Biotechnol. 2017 May;44(4-5):687-695. – form PTO-892) reviews protein engineering techniques, such as random mutagenesis and recombination, directed evolution and iterative or combinatory saturation “hotspots”. Fransceus states that “a recurring problem, however, is choosing which amino acid positions should be targeted. Answering this question is not an easy feat and requires substantial insight in the relationship between an enzyme’s sequence or structure and its properties.” Sanavia (Computational and Structural Biotechnology Journal, Volume 18, 2020, Pages 1968-1979. – form PTO-892) discloses challenges in the prediction of protein stability in the occurrence of multiple mutations. “Multiple-point mutations are common variations of the protein sequence that may be needed in protein engineering when a single-point mutation is not enough to yield the desired stability change. Dealing with multiple-site variations adds another level of complexity beyond the prediction of the effect of a single variant on protein stability, since it requires the learning of many types of combinatorial effects”.
An important consideration is that structure is not necessarily a reliable indicator of function. In the instant case, there is no disclosure relating similarity of structure to conservation of function. Conservation of structure is not necessarily a surrogate for conservation of function.
Given this lack of description of the representative species encompassed by the genus of the claims, the specification fails to sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that applicants were in possession of the inventions of claims 1-3, 6, 9, 12, 15, 18-20, 22, 24-26, 28, 30-33, 35-37, 39, 42, 46, 54-56, 58-59, and 62.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 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 –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-2, 6, 9, 12, 15, 18-19, 26, 35-36, 42, 46, 59, and 62 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Aivado (US 2017/0114098 - PTO-892).
Regarding claims 1-2, Aivado discloses a method of treating cancer in a patient by administering to the patient (a) an effective amount of an L-asparaginase and (b) an anti-cancer agent, a small molecule or antibody, selected from (i) an inhibitor of BCL-XL, (ii) an inhibitor of BCL-2, (iii) an inhibitor of both BCL-XL and BCL-2, (iv) a mTOR inhibitor, (v) a CD20 inhibitor, or (vi) a BTK inhibitor (abstract, [0003], [0107], [0118], [0125]-[0126], [0133], and [0750]).
Regarding claim 6, Aivado discloses that the inhibitor of BCL-2 is venetoclax (ABT-199) ([0126]).
Regarding claim 9 Aivado discloses that the inhibitor of both BCL-XL and BCL-2 is navitoclax (ABT-263) ([0126]).
Regarding claim 12, Aivado discloses that the inhibitor of mTOR is everolimus ([0125]).
Regarding claim 15, Aivado discloses that the inhibitor of CD20 is rituximab ([0118]).
Regarding claim 18, Aivado discloses that the inhibitor of BTK is ibrutinib ([0750]).
Regarding claim 19, Aivado discloses that the cancer has an NRAS mutation ([0657]).
Regarding claim 26, the patients of Aivado are adults and/or pediatrics since adults and children are diagnosed with cancer ([0702]).
Regarding claim 35, Aivado discloses that the cancer is lymphoma, ALL or AML ([0385]).
Regarding claims 36, 46, 59, and 62, Aivado discloses that the cancer is a solid cancer, such as triple negative breast cancer (TNBC), pancreatic cancer, lung cancer, ovarian cancer, gastric cancer, sarcoma, or colorectal cancer ([0375] and [0377]). The asparaginase of Aivado is unfunctionalized ([0133]).
Regarding claim 42, Aivado discloses that the lymphoma is Burkitt lymphoma ([0385]).
Therefore, the reference of Aivado anticipates claims 1-2, 6, 9, 12, 15, 18-19, 26, 35-36, 42, 46, 59, and 62.
Claim(s) 1-2, 6, 20, 22, 26, 30-31, 33, 35-36, 39, 54-56, and 58 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Emadi (WO 2020/132184 – form PTO-1449).
Regarding claims 1-2, 6, 20, 22, 35, and 39, Emadi discloses a method treating cancer, such as AML, R/R AML, or ALL, by administering a therapeutically effective amount of (i) Erwinia chrysanthemi L-asparaginase and (2) an agent that inhibits BCL-2, such as venetoclax (Ven), a small molecule (abstract, [0002]-[0005], and [0012]). Erwinia chrysanthemi L-asparaginase has 100% sequence identity to the Erwinia chrysanthemi L-asparaginase of SEQ ID NO:1 of the instant application (see the sequence alignment below).
Regarding claim 26, Emadi discloses pediatric and/or adult patients ([0003] and [0053]).
Regarding claim 30, the Erwinia chrysanthemi L-asparaginase of Emadi is unfunctionalized ([0003] and [0012]).
Regarding claim 31, the Erwinia chrysanthemi L-asparaginase of Emadi is recombinantly produced from Pseudomonas fluorescens ([0012]).
Regarding claim 33, Emaldi discloses administering L-asparaginase conjugated to a PEG moiety ([0012]).
Regarding claim 36, Emaldi discloses treating breast cancer, colorectal cancer, ovarian cancer, lymphoma, lung cancer, pancreatic cancer, or gastric cancer ([0015]).
Regarding claim 54, Emaldi discloses monitoring levels of BCL2 expression as a prognostic marker to determine treatment ([00139]). Cancers exhibit overexpression of BCL2 ([0014]).
Regarding claims 55-56, Emaldi discloses administering a glutaminase inhibitor or CB-839 ([0087]). Emaldi discloses that inhibition of glutaminase was reported to sensitize AML cells to venetoclax ([0044]).
Regarding claim 58, Emaldi discloses a method of treating NRAS mutant AML by administering an effective amount of an L-asparaginase (abstract, [0002]-[0005], [0012], and [0086]).
Therefore, the reference of Emaldi anticipates 1-2, 6, 20, 22, 26, 30-31, 33, 35-36, 39, 54-56, and 58.
Claim(s) 1-3 and 35 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Khan (A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat Med 25, 1938–1947 (2019). – form PTO-1449).
Regarding claims 1-3 and 35, Khan discloses a method of treating cancer or ALL by administering an effective amount of (a) asparaginase and (b) DT2216, a small molecule inhibitor of BCL-XL (page 1945).
Therefore, the reference of Khan anticipates claims 1-3 and 35.
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.
Claim(s) 1-2, 6, 9, 12, 15, 18-20, 22, 24-26, 30-31, 33, 35-36, 39, 42, 46, 54-56, 58, 59, and 62 is/are rejected under 35 U.S.C. 103 as being unpatentable over Aivado (US 2017/0114098 - PTO-892), Emadi (WO 2020/132184 – form PTO-1449), and Brigitha (Hypersensitivity to Pegylated E.coli asparaginase as first-line treatment in contemporary paediatric acute lymphoblastic leukaemia protocols: a meta-analysis of the Ponte di Legno Toxicity working group. Eur J Cancer. 2022 Feb;162:65-75. Epub 2021 Dec 23 – form PTO-892).
Regarding claims 1-2, Aivado discloses a method of treating cancer in a patient by administering to the patient (a) an effective amount of an L-asparaginase and (b) an anti-cancer agent, a small molecule or antibody, selected from (i) an inhibitor of BCL-XL, (ii) an inhibitor of BCL-2, (iii) an inhibitor of both BCL-XL and BCL-2, (iv) a mTOR inhibitor, (v) a CD20 inhibitor, or (vi) a BTK inhibitor (abstract, [0003], [0107], [0118], [0125]-[0126], [0133], and [0750]).
Regarding claim 6, Aivado discloses that the inhibitor of BCL-2 is venetoclax (ABT-199) ([0126]).
Regarding claim 9 Aivado discloses that the inhibitor of both BCL-XL and BCL-2 is navitoclax (ABT-263) ([0126]).
Regarding claim 12, Aivado discloses that the inhibitor of mTOR is everolimus ([0125]).
Regarding claim 15, Aivado discloses that the inhibitor of CD20 is rituximab ([0118]).
Regarding claim 18, Aivado discloses that the inhibitor of BTK is ibrutinib ([0750]).
Regarding claim 19, Aivado discloses that the cancer has an NRAS mutation ([0657]).
Regarding claim 26, the patients of Aivado are adults and/or pediatrics since adults and children are diagnosed with cancer ([0702]).
Regarding claim 35, Aivado discloses that the cancer is lymphoma, ALL or AML ([0385]).
Regarding claims 36, 46, 59, and 62, Aivado discloses that the cancer is a solid cancer, such as triple negative breast cancer (TNBC), pancreatic cancer, lung cancer, ovarian cancer, gastric cancer, sarcoma, or colorectal cancer ([0375] and [0377]). The asparaginase of Aivado is unfunctionalized ([0133]).
Regarding claim 42, Aivado discloses that the lymphoma is Burkitt lymphoma ([0385]).
Aivado does not disclose administering Erwinia chrysanthemi L-asparaginase having 80-100% sequence identity to SEQ ID NO:1 of the instant application, administering a glutaminase inhibitor or CB-839, and patients exhibiting hypersensitivity to E. coli derived asparaginase.
Regarding claims 1-2, 6, 20, 22, 35, and 39, Emadi discloses a method treating cancer, such as AML, R/R AML, or ALL, by administering a therapeutically effective amount of (i) Erwinia chrysanthemi L-asparaginase and crisantaspase (homotetramer)and (2) an agent that inhibits BCL-2, such as venetoclax (Ven), a small molecule (abstract, [0002]-[0005], and [0012]). Erwinia chrysanthemi L-asparaginase has 100% sequence identity to the Erwinia chrysanthemi L-asparaginase of SEQ ID NO:1 of the instant application and exists as a homotetramer (see the sequence alignment below).
Regarding claim 26, Emadi discloses pediatric and/or adult patients ([0003] and [0053]).
Regarding claim 30, the Erwinia chrysanthemi L-asparaginase of Emadi is unfunctionalized ([0003] and [0012]).
Regarding claim 31, the Erwinia chrysanthemi L-asparaginase of Emadi is recombinantly produced from Pseudomonas fluorescens ([0012]).
Regarding claim 33, Emaldi discloses administering L-asparaginase conjugated to a PEG moiety ([0012]).
Regarding claim 36, Emaldi discloses treating breast cancer, colorectal cancer, ovarian cancer, lymphoma, lung cancer, pancreatic cancer, or gastric cancer ([0015]).
Regarding claim 54, Emaldi discloses monitoring levels of BCL2 expression as a prognostic marker to determine treatment ([00139]). Cancers exhibit overexpression of BCL2 ([0014]).
Regarding claims 55-56, Emaldi discloses administering a glutaminase inhibitor or CB-839 ([0087]). Emaldi discloses that inhibition of glutaminase was reported to sensitize AML cells to venetoclax ([0044]).
Regarding claim 58, Emaldi disclsoes a method of treating NRAS mutant AML by administering an effective amount of an L-asparaginase (abstract, [0002]-[0005], [0012], and [0086]).
Regarding claims 1, 24-26, and 35, Brigitha discloses that administration of E. coli asparaginase to treat ALL results in hypersensitivity to said asparaginase in adult and pediatric patients (abstract).
Therefore, in combining the teachings of the above references, it would have been obvious to one having ordinary skill in the art before the time the claimed invention was effectively filed to modify the method of Aivado by administering Erwinia chrysanthemi L-asparaginase or pegylated Erwinia chrysanthemi L-asparaginase and a glutaminase inhibitor to a patient having terminated E. coli asparaginase therapy due to hypersensitivity to E. coli derived asparaginase, and measuring BCL-2 expression in a sample derived from the patient. One having ordinary skill in the art would have been motivated to do so because some patients develop hypersensitivity to E. coli asparaginase, inhibition of glutaminase sensitizes AML cells to venetoclax, and BCL-2 can be used as a prognostic marker since cancer cells overexpress BCL-2. One having ordinary skill in the art would have has a reasonable expectation of success since Aivado teaches a method of treating a variety of cancers by administering an asparaginase and inhibitors of BCL-XL, BCL-2, both BCL-XL and BCL-2, mTOR, CD20, and BTK, Emaildi teaches a method of treating AML or ALL by administering Erwinia chrysanthemi L-asparaginase, a glutaminase inhibitor, and inhibitors of BCL-2, and Brigitha teaches that administration of E. coli asparaginase to treat ALL results in hypersensitivity to said asparaginase in adult and pediatric patients
Therefore, the above references render claims 1-2, 6, 9, 12, 15, 18-20, 22, 24-26, 30-31, 33, 35-36, 39, 42, 46, 54-56, 58, 59, and 62 prima facie obvious.
Claim(s) 28, 32, and 37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Aivado (US 2017/0114098 - PTO-892), Emadi (WO 2020/132184 – form PTO-1449), and Brigitha (Hypersensitivity to Pegylated E.coli asparaginase as first-line treatment in contemporary paediatric acute lymphoblastic leukaemia protocols: a meta-analysis of the Ponte di Legno Toxicity working group. Eur J Cancer. 2022 Feb;162:65-75. Epub 2021 Dec 23 – form PTO-892) as applied to claims 1-2, 6, 9, 12, 15, 18-20, 22, 24-26, 30-31, 33, 35-36, 39, 42, 46, 54-56, 58, 59, and 62 above, and further in view of Choi (WO 2021/078988 - form PTO-892) and Chen (Disruption of β-Catenin-Dependent Wnt Signaling in Colon Cancer Cells Remodels the Microenvironment to Promote Tumor Invasion. Mol Cancer Res. 2022 Mar 1;20(3):468-484. – form PTO-892).
Aivado, Emadi, and Brigitha do not disclose L-asparaginase having less than 6% aggregation, using NSAA assay, and treating wnt-negative colorectal cancer.
Regarding claims 1, 20, 22, and 28, Choi discloses an Erwinia chrysanthemi L-asparaginase with less than 1% aggregation ([0017]). The Erwinia chrysanthemi L-asparaginase has 100% sequence identity to the Erwinia chrysanthemi L-asparaginase of SEQ ID NO:1 of the instant application and exists as a homotetramer ([0020] and see the sequence alignment below).
Regarding claim 32, Choi discloses using a nadir serum asparaginase activity (NSAA) assay as measured from a serum sample from the human subject, wherein the asparaginase equals or exceeds 0.1 IU/mL after administration after treatment with the recombinant L-asparaginase ([0016]).
Regarding claim 37, Chen discloses that a subset of colorectal cancer is a Wnt-negative colorectal cancer and has poor patient outcome in early-invasive colon cancer (abstract).
Therefore, in combining the teachings of the above references, it would have been obvious to one having ordinary skill in the art before the time the claimed invention was effectively filed to further modify the method taught by the combined teachings of Aivado, Emadi, and Brigitha by administering an L-asparaginase having less than 1% aggregation, using NSAA assay, and treat Wnt-negative colorectal cancer. One having ordinary skill in the art would have been motivated to do so because the L-asparaginase of Choi has very low aggregation, NSAA assay can be used to monitor the treatment, and Wnt-negative colorectal cancer has poor patient outcome. One having ordinary skill in the art would have has a reasonable expectation of success since Aivado teaches a method of treating a variety of cancers by administering an asparaginase and inhibitors of BCL-XL, BCL-2, both BCL-XL and BCL-2, mTOR, CD20, and BTK, Emaildi teaches a method of treating AML or ALL by administering Erwinia chrysanthemi L-asparaginase, a glutaminase inhibitor, and inhibitors of BCL-2, Brigitha teaches that administration of E. coli asparaginase to treat ALL results in hypersensitivity to said asparaginase in adult and pediatric patients, Choi teaches L-asapraghinse having less than 1% aggregation, Choi teaches NSAA assay, and Chen teaches wnt-negative colorectal cancer.
Therefore, the above references render claims 1-2, 6, 9, 12, 15, 18-20, 22, 24-26, 28, 30-33, 35-37, 39, 42, 46, 54-56, 58, 59, and 62 prima facie obvious.
Conclusion
Claims 1-3, 6, 9, 12, 15, 18-20, 22, 24-26, 28, 30-33, 35-37, 39, 42, 46, 54-56, 58-59, and 62 are pending.
Claims 1-3, 6, 9, 12, 15, 18-20, 22, 24-26, 28, 30-33, 35-37, 39, 42, 46, 54-56, 58, 59, and 62 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to YONG D PAK whose telephone number is (571)272-0935. The examiner can normally be reached M-Th: 5:30 am - 3:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached on 408-918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/YONG D PAK/Primary Examiner, Art Unit 1652
Sequence alignment of the asparaginase of SEQ ID NO:1 of the instant application (“Qy”) and Erwinia chrysanthemi asparaginase (“Db”)
ASPG_DICCH
ID ASPG_DICCH Reviewed; 348 AA.
AC P06608;
DT 01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1988, sequence version 1.
DT 10-JUN-2026, entry version 121.
DE RecName: Full=L-asparaginase;
DE Short=L-ASNase;
DE EC=3.5.1.1;
DE AltName: Full=L-asparagine amidohydrolase;
DE Flags: Precursor;
GN Name=ansB; Synonyms=asn;
OS Dickeya chrysanthemi (Pectobacterium chrysanthemi) (Erwinia chrysanthemi).
OC Bacteria; Pseudomonadati; Pseudomonadota; Gammaproteobacteria;
OC Enterobacterales; Pectobacteriaceae; Dickeya.
OX NCBI_TaxID=556;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=NCPPB 1066;
RX PubMed=3026924; DOI=10.1016/0378-1119(86)90163-0;
RA Minton N.P., Bullman H.M.S., Scawen M.D., Atkinson T., Gilbert H.J.;
RT "Nucleotide sequence of the Erwinia chrysanthemi NCPPB 1066 L-asparaginase
RT gene.";
RL Gene 46:25-35(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=NCPPB 1125;
RX PubMed=3194219; DOI=10.1093/nar/16.21.10385;
RA Filpula D., Nagle J.W., Pulford S., Anderson D.M.;
RT "Sequence of L-asparaginase gene from Erwinia chrysanthemi NCPPB 1125.";
RL Nucleic Acids Res. 16:10385-10385(1988).
RN [3]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS).
RX PubMed=3379033; DOI=10.1016/s0021-9258(18)68344-9;
RA Tanaka S., Robinson E.A., Appella E., Miller M., Ammon H.L., Roberts J.,
RA Weber I.T., Wlodawer A.;
RT "Structures of amidohydrolases. Amino acid sequence of a glutaminase-
RT asparaginase from Acinetobacter glutaminasificans and preliminary
RT crystallographic data for an asparaginase from Erwinia chrysanthemi.";
RL J. Biol. Chem. 263:8583-8591(1988).
RN [4]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) IN COMPLEX WITH ASPARTIC ACID, ACTIVE
RP SITE, AND SUBUNIT.
RX PubMed=8348975; DOI=10.1016/0014-5793(93)80943-o;
RA Miller M.M., Rao J.K.M., Wlodawer A., Gribskov M.R.;
RT "A left-handed crossover involved in amidohydrolase catalysis. Crystal
RT structure of Erwinia chrysanthemi L-asparaginase with bound L-aspartate.";
RL FEBS Lett. 328:275-279(1993).
RN [5]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 22-348 IN COMPLEXES WITH GLUTAMIC
RP ACID; ASPARTIC ACID AND SUCCINIC ACID.
RX PubMed=11341830; DOI=10.1021/bi0029595;
RA Aghaiypour K., Wlodawer A., Lubkowski J.;
RT "Structural basis for the activity and substrate specificity of Erwinia
RT chrysanthemi L-asparaginase.";
RL Biochemistry 40:5655-5664(2001).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 22-348 IN COMPLEX WITH INHIBITOR
RP 6-DIAZO-5-OXY-NORLEUCINE, AND ACTIVE SITE.
RX PubMed=11755201; DOI=10.1016/s0167-4838(01)00270-9;
RA Aghaiypour K., Wlodawer A., Lubkowski J.;
RT "Do bacterial L-asparaginases utilize a catalytic triad Thr-Tyr-Glu?";
RL Biochim. Biophys. Acta 1550:117-128(2001).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (1.0 ANGSTROMS) OF 22-348, AND SUBUNIT.
RX PubMed=12499544; DOI=10.1107/s0907444902019443;
RA Lubkowski J., Dauter M., Aghaiypour K., Wlodawer A., Dauter Z.;
RT "Atomic resolution structure of Erwinia chrysanthemi L-asparaginase.";
RL Acta Crystallogr. D 59:84-92(2003).
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-asparagine + H2O = L-aspartate + NH4(+);
CC Xref=Rhea:RHEA:21016, ChEBI:CHEBI:15377, ChEBI:CHEBI:28938,
CC ChEBI:CHEBI:29991, ChEBI:CHEBI:58048; EC=3.5.1.1;
CC -!- SUBUNIT: Homotetramer. {ECO:0000269|PubMed:11755201,
CC ECO:0000269|PubMed:12499544, ECO:0000269|PubMed:8348975}.
CC -!- PHARMACEUTICAL: Available under the name Erwinase (Beaufour Ipsen).
CC Used as an antineoplastic in chemotherapy. Reduces the quantity of
CC asparagine available to cancer cells.
CC -!- MISCELLANEOUS: The sequence of strain NCPPB 1066 is shown.
CC -!- SIMILARITY: Belongs to the asparaginase 1 family. {ECO:0000305}.
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DR EMBL; X14777; CAA32884.1; -; Genomic_DNA.
DR EMBL; X12746; CAA31239.1; -; Genomic_DNA.
DR PIR; A26054; A26054.
DR PDB; 1HFJ; X-ray; 2.40 A; A/C=22-348.
DR PDB; 1HFK; X-ray; 2.17 A; A/C=22-348.
DR PDB; 1HFW; X-ray; 1.80 A; A/B/C/D=22-348.
DR PDB; 1HG0; X-ray; 1.90 A; A/B/C/D=22-348.
DR PDB; 1HG1; X-ray; 1.80 A; A/B/C/D=22-348.
DR PDB; 1JSL; X-ray; 1.70 A; A/B/C/D=22-348.
DR PDB; 1JSR; X-ray; 1.70 A; A/B/C/D=22-348.
DR PDB; 1O7J; X-ray; 1.00 A; A/B/C/D=22-348.
DR PDB; 5F52; X-ray; 1.63 A; A/B/C/D=23-348.
DR PDB; 5HW0; X-ray; 1.70 A; A/B/C/D=23-348.
DR PDB; 5I3Z; X-ray; 2.05 A; A/B/C/D=23-348.
DR PDB; 5I48; X-ray; 1.50 A; A/B/C/D=23-348.
DR PDB; 5I4B; X-ray; 1.60 A; A/B/C=23-348.
DR PDB; 6PAE; X-ray; 1.60 A; A/B/C/D=22-348.
DR PDB; 7U6M; X-ray; 1.75 A; A/B/C/D=23-348.
DR PDB; 8WGQ; X-ray; 2.75 A; A/B/C/D=22-348.
DR PDBsum; 1HFJ; -.
DR PDBsum; 1HFK; -.
DR PDBsum; 1HFW; -.
DR PDBsum; 1HG0; -.
DR PDBsum; 1HG1; -.
DR PDBsum; 1JSL; -.
DR PDBsum; 1JSR; -.
DR PDBsum; 1O7J; -.
DR PDBsum; 5F52; -.
DR PDBsum; 5HW0; -.
DR PDBsum; 5I3Z; -.
DR PDBsum; 5I48; -.
DR PDBsum; 5I4B; -.
DR PDBsum; 6PAE; -.
DR PDBsum; 7U6M; -.
DR PDBsum; 8WGQ; -.
DR AlphaFoldDB; P06608; -.
DR SMR; P06608; -.
DR ChEMBL; CHEMBL1075190; -.
DR DrugBank; DB02233; 6-hydroxy-D-norleucine.
DR DrugBank; DB03412; 6-hydroxynorleucine.
DR DrugBank; DB02655; D-Aspartic Acid.
DR Allergome; 8366; Erw ch Asparaginase.
DR BRENDA; 3.5.1.1; 2141.
DR EvolutionaryTrace; P06608; -.
DR GO; GO:0004067; F:asparaginase activity; IEA:UniProtKB-EC.
DR GO; GO:0006520; P:amino acid metabolic process; IEA:InterPro.
DR GO; GO:0006528; P:asparagine metabolic process; IEA:InterPro.
DR CDD; cd00411; L-asparaginase_like; 1.
DR FunFam; 3.40.50.1170:FF:000001; L-asparaginase 2; 1.
DR Gene3D; 3.40.50.40; -; 1.
DR Gene3D; 3.40.50.1170; L-asparaginase, N-terminal domain; 1.
DR InterPro; IPR004550; AsnASE_II.
DR InterPro; IPR036152; Asp/glu_Ase-like_sf.
DR InterPro; IPR006034; Asparaginase/glutaminase-like.
DR InterPro; IPR020827; Asparaginase/glutaminase_AS1.
DR InterPro; IPR027475; Asparaginase/glutaminase_AS2.
DR InterPro; IPR040919; Asparaginase_C.
DR InterPro; IPR027473; L-asparaginase_C.
DR InterPro; IPR027474; L-asparaginase_N.
DR InterPro; IPR037152; L-asparaginase_N_sf.
DR NCBIfam; TIGR00520; asnASE_II; 1.
DR PANTHER; PTHR11707:SF28; 60 KDA LYSOPHOSPHOLIPASE; 1.
DR PANTHER; PTHR11707; L-ASPARAGINASE; 1.
DR Pfam; PF00710; Asparaginase; 1.
DR Pfam; PF17763; Asparaginase_C; 1.
DR PIRSF; PIRSF001220; L-ASNase_gatD; 1.
DR PIRSF; PIRSF500176; L_ASNase; 1.
DR PRINTS; PR00139; ASNGLNASE.
DR SMART; SM00870; Asparaginase; 1.
DR SUPFAM; SSF53774; Glutaminase/Asparaginase; 1.
DR PROSITE; PS00144; ASN_GLN_ASE_1; 1.
DR PROSITE; PS00917; ASN_GLN_ASE_2; 1.
DR PROSITE; PS51732; ASN_GLN_ASE_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Hydrolase; Pharmaceutical; Signal.
FT SIGNAL 1..21
FT CHAIN 22..348
FT /note="L-asparaginase"
FT /id="PRO_0000002358"
FT DOMAIN 26..348
FT /note="Asparaginase/glutaminase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01068"
FT ACT_SITE 36
FT /note="O-isoaspartyl threonine intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10099,
FT ECO:0000255|PROSITE-ProRule:PRU10100,
FT ECO:0000269|PubMed:11755201, ECO:0000269|PubMed:8348975"
FT BINDING 83
FT /ligand="substrate"
FT BINDING 116..117
FT /ligand="substrate"
FT VARIANT 177
FT /note="L -> I (in strain: NCPPB 1125)"
FT VARIANT 199
FT /note="K -> R (in strain: NCPPB 1125)"
FT VARIANT 288
FT /note="M -> L (in strain: NCPPB 1125)"
FT VARIANT 295
FT /note="I -> M (in strain: NCPPB 1125)"
FT STRAND 27..35
FT /evidence="ECO:0007829|PDB:1O7J"
FT HELIX 36..38
FT /evidence="ECO:0007829|PDB:1O7J"
FT STRAND 42..45
FT /evidence="ECO:0007829|PDB:5HW0"
FT STRAND 48..50
FT /evidence="ECO:0007829|PDB:5F52"
FT STRAND 51..53
FT /evidence="ECO:0007829|PDB:1O7J"
FT HELIX 57..63
FT /evidence="ECO:0007829|PDB:1O7J"
FT HELIX 65..69
FT /evidence="ECO:0007829|PDB:1O7J"
FT STRAND 72..81
FT /evidence="ECO:0007829|PDB:1O7J"
FT HELIX 83..85
FT /evidence="ECO:0007829|PDB:1O7J"
Query Match 100.0%; Score 1644; Length 348;
Best Local Similarity 100.0%;
Matches 327; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ADKLPNIVILATGGTIAGSAATGTQTTGYKAGALGVDTLINAVPEVKKLANVKGEQFSNM 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 22 ADKLPNIVILATGGTIAGSAATGTQTTGYKAGALGVDTLINAVPEVKKLANVKGEQFSNM 81
Qy 61 ASENMTGDVVLKLSQRVNELLARDDVDGVVITHGTDTVEESAYFLHLTVKSDKPVVFVAA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 82 ASENMTGDVVLKLSQRVNELLARDDVDGVVITHGTDTVEESAYFLHLTVKSDKPVVFVAA 141
Qy 121 MRPATAISADGPMNLLEAVRVAGDKQSRGRGVMVVLNDRIGSARYITKTNASTLDTFKAN 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 142 MRPATAISADGPMNLLEAVRVAGDKQSRGRGVMVVLNDRIGSARYITKTNASTLDTFKAN 201
Qy 181 EEGYLGVIIGNRIYYQNRIDKLHTTRSVFDVRGLTSLPKVDILYGYQDDPEYLYDAAIQH 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 202 EEGYLGVIIGNRIYYQNRIDKLHTTRSVFDVRGLTSLPKVDILYGYQDDPEYLYDAAIQH 261
Qy 241 GVKGIVYAGMGAGSVSVRGIAGMRKAMEKGVVVIRSTRTGNGIVPPDEELPGLVSDSLNP 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 262 GVKGIVYAGMGAGSVSVRGIAGMRKAMEKGVVVIRSTRTGNGIVPPDEELPGLVSDSLNP 321
Qy 301 AHARILLMLALTRTSDPKVIQEYFHTY 327
|||||||||||||||||||||||||||
Db 322 AHARILLMLALTRTSDPKVIQEYFHTY 348
Sequence alignment of the asparaginase of SEQ ID NO:1 of the instant application (“Qy”) and Erwinia chrysanthemi asparaginase of SEQ ID NO:1 of Choi (“Db”)
BJG55223
ID BJG55223 standard; protein; 327 AA.
XX
AC BJG55223;
XX
DT 10-JUN-2021 (first entry)
XX
DE Erwinia chrysanthemi recombinant L-asparaginase, SEQ ID: 1.
XX
KW Asparaginase; Asparagine depletion; L-asparaginase;
KW acute lymphoblastic leukemia; breast tumor; cancer; colorectal tumor;
KW cytostatic; head and neck tumor; liver tumor; metastatic breast cancer;
KW prostate tumor; protein therapy; sarcoma; stomach tumor; therapeutic.
XX
OS Erwinia chrysanthemi; strain NCPPB 1066.
XX
CC PN WO2021078988-A1.
XX
CC PD 29-APR-2021.
XX
CC PF 23-OCT-2020; 2020WO-EP079972.
XX
PR 25-OCT-2019; 2019US-0926201P.
PR 01-JUL-2020; 2020US-0047222P.
XX
CC PA (JAZZ-) JAZZ PHARM IRELAND LTD.
XX
CC PI Choi MR, Lin T, Silverman J;
XX
DR WPI; 2021-425690/041.
DR GENBANK; CAA32884.
XX
CC PT Treating disease treatable by asparagine depletion e.g. acute
CC PT lymphoblastic leukemia, lymphoblastic lymphoma, sarcoma, breast cancer,
CC PT liver cancer, prostate cancer, colorectal cancer, by administering
CC PT recombinant L-asparaginase.
XX
CC PS Claim 1; SEQ ID NO 1; 173pp; English.
XX
CC The present invention relates to a method useful for treating disease by
CC asparagine depletion. The method involves administering a recombinant L-
CC asparaginase or its composition to the human subject, where the
CC recombinant L- asparaginase is a tetramer and is recombinantly produced
CC in Pseudomonas fluorescens. The method of the invention is useful for
CC treating cancer, where cancer is selected from sarcoma, acute
CC lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LBL), breast
CC cancer, metastatic breast cancer, liver cancer, stomach cancer, prostate
CC cancer, colorectal cancer, and head and neck cancer and exhibits an
CC excellent synergistic therapeutic effect without causing adverse side
CC effects.
XX
SQ Sequence 327 AA;
Query Match 100.0%; Score 1644; Length 327;
Best Local Similarity 100.0%;
Matches 327; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ADKLPNIVILATGGTIAGSAATGTQTTGYKAGALGVDTLINAVPEVKKLANVKGEQFSNM 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ADKLPNIVILATGGTIAGSAATGTQTTGYKAGALGVDTLINAVPEVKKLANVKGEQFSNM 60
Qy 61 ASENMTGDVVLKLSQRVNELLARDDVDGVVITHGTDTVEESAYFLHLTVKSDKPVVFVAA 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ASENMTGDVVLKLSQRVNELLARDDVDGVVITHGTDTVEESAYFLHLTVKSDKPVVFVAA 120
Qy 121 MRPATAISADGPMNLLEAVRVAGDKQSRGRGVMVVLNDRIGSARYITKTNASTLDTFKAN 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 MRPATAISADGPMNLLEAVRVAGDKQSRGRGVMVVLNDRIGSARYITKTNASTLDTFKAN 180
Qy 181 EEGYLGVIIGNRIYYQNRIDKLHTTRSVFDVRGLTSLPKVDILYGYQDDPEYLYDAAIQH 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 EEGYLGVIIGNRIYYQNRIDKLHTTRSVFDVRGLTSLPKVDILYGYQDDPEYLYDAAIQH 240
Qy 241 GVKGIVYAGMGAGSVSVRGIAGMRKAMEKGVVVIRSTRTGNGIVPPDEELPGLVSDSLNP 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 GVKGIVYAGMGAGSVSVRGIAGMRKAMEKGVVVIRSTRTGNGIVPPDEELPGLVSDSLNP 300
Qy 301 AHARILLMLALTRTSDPKVIQEYFHTY 327
|||||||||||||||||||||||||||
Db 301 AHARILLMLALTRTSDPKVIQEYFHTY 327
Prosecution Insights