Office Action 1: Non-Final Rejection (2024-06-06)
Rejection types: 101 - Patent-Eligible Subject Matter, Double Patenting

CLAIMS:
AMENDMENTS TO THE CLAIMS Set forth below in ascending order, with status identifiers, is a complete listing of all claims currently under examination. Changes to any amended claims are indicated by \[\[double brackets\]\], and or underlining. This listing also reflects any cancellation and or addition of claims.

1\. (Original) A method for detecting a colon cancer in a subject in need thereof, comprising:
determining the expression level of at least 14 biomarkers from a test sample from the subject by contacting the test sample with a plurality of agents specific to detect the expression of the at least 14 biomarkers, wherein the 14 biomarkers comprise ADRMI, CDK4, COMT, DHCR7, HMOX2, MCM2, PDXK, POP7, SlOOP, SNRPA, SORD, STOML2, LIMPS, and a housekeeping gene;
normalizing the expression level of each of ADRMI, CDK4, COMT, DHCR7, HMOX2, MCM2, PDXK, POP 7, SlOOP, SNRPA, SORD, STOML2, and UMPS to the expression level of the housekeeping gene, thereby obtaining a normalized expression level of each of ADRMI, CDK4, COMT, DHCR7, HMOX2, MCM2, PDXK, POP 7, SlOOP, SNRPA, SORD, STOML2, and LIMPS;
inputting each normalized expression level into an algorithm to generate a score;
comparing the score with a predetermined cutoff value; and
producing a report, wherein the report identifies the presence of a colon cancer in the subject when the score is equal to or greater than the predetermined cutoff value or identifies the absence of a colon cancer in the subject when the score is less than the predetermined cutoff value.

2\. (Original) A method for determining whether a colon cancer in a subject is stable or progressive, the method comprising:
determining the expression level of at least 14 biomarkers from a test sample from the subject by contacting the test sample with a plurality of agents specific to detect the expression of the at least 14 biomarkers, wherein the 14 biomarkers comprise ADRMI, CDK4, COMT, DHCR7, HMOX2, MCM2, PDXK, POP7, SlOOP, SNRPA, SORD, STOML2, LIMPS, and a housekeeping gene;
normalizing the expression level of each of ADRMI, CDK4, COMT, DHCR7, HMOX2, MCM2, PDXK, POP 7, SlOOP, SNRPA, SORD, STOML2, and UMPS to the expression level of the housekeeping gene, thereby obtaining a normalized expression level of each of ADRMI, CDK4, COMT, DHCR7, HMOX2, MCM2, PDXK, POP 7, SlOOP, SNRPA, SORD, STOML2, and LIMPS;
inputting each normalized expression level into an algorithm to generate a score;
comparing the score with a predetermined cutoff value; and
producing a report, wherein the report identifies that the colon cancer is progressive when the score is equal to or greater than the predetermined cutoff value or identifies that the colon cancer is stable when the score is less than the predetermined cutoff value.

3\. - 31. (Canceled) 430

32\. (New) A method of treating colon cancer in a subject comprising:
determining the expression level of at least 14 biomarkers from a test sample from a subject by contacting the test sample with a plurality of agents specific to detect the expression of the at least 14 biomarkers, wherein the 14 biomarkers comprise ADRMI, CDK4, COMT, DHCR7, HMOX2, MCM2, PDXK, POP7, SlOOP, SNRPA, SORD, STOML2, LIMPS, and a housekeeping gene, wherein the housekeeping gene is MORF4LJ;
normalizing the expression level of each of ADRMI, CDK4, COMT, DHCR7, HMOX2, MCM2, PDXK, POP 7, SlOOP, SNRPA, SORD, STOML2, and UMPS to the expression level of the housekeeping gene, thereby obtaining a normalized expression level of each of ADRMI, CDK4, COMT, DHCR7, HMOX2, MCM2, PDXK, POP 7, SlOOP, SNRPA, SORD, STOML2, and LIMPS; inputting each normalized expression level into an algorithm to generate a score, wherein the algorithm is a product of a model of colon cancer disease derived using the XGB algorithm;
comparing the score with a predetermined cutoff value;
determining that the score is equal to or greater than the predetermined cutoff value, thereby identifying the subject as having colon cancer; and
administering to the subject identified as having colon cancer a therapy, wherein the therapy comprises anti-cancer therapy, chemotherapy, targeted drug therapy, radiation therapy, immunotherapy or any combination thereof.

33\. (New) The method of claim 32, wherein the predetermined cutoff value is at least 50% on a scale of 0-100%.

34\. (New) The method of claim 32, wherein the predetermined cutoff value is at least 60% on a scale of 0-100%.

35\. (New) The method of claim 32, wherein the predetermined cutoff value has a sensitivity of identifying the subject as having colon cancer that is greater than 85%.

36\. (New) The method of claim 32, wherein the predetermined cutoff value has a specificity of identifying the subject as having colon cancer that is greater than 75%.

37\. (New) The method of claim 32, wherein at least one of the at least 14 biomarkers is RNA, cDNA or protein.

38\. (New) The method of claim 37, wherein when the biomarker is RNA, the RNA is reverse transcribed to produce cDNA, and the produced cDNA expression level is detected.

39\. (New) The method of claim 32, wherein the predetermined cutoff value is derived from a plurality of reference samples obtained from subjects not having or not diagnosed with a colon cancer.

40\. (New) The method of claim 32, wherein therapy comprises chemotherapy, wherein the chemotherapy comprises FOLFOX, FOLFIRI, a combination of 5-FU and leucovorin, capecitabine, irinotecan, CapeOx or any combination thereof.

41\. (New) The method of claim 32, wherein when the therapy comprises targeted drug therapy, wherein the targeted drug therapy comprises bevacizumab, cetuximab, panitumumab, regorafenib, a combination of trifluridine and tipiracil, an EGFR TKI inhibitor or any combination thereof.

42\. (New) The method of claim 32, wherein when the therapy comprises anti-cancer therapy, wherein the anticancer therapy comprises anti-colon cancer therapy.

43\. (New) The method of claim 32, wherein when the therapy comprises immunotherapy, wherein the immunotherapy comprises pembrolizumab, nivolumab or a combination of pembrolizumab and nivolumab.
2 3 4 5 283932919 v1

OFFICE ACTION:
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 .
Claims 1, 2, and newly added claims 32-43 are pending and under examination.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1 and 2 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature and an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014).  See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014.  The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to methods and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claimed invention recites a method of detecting colon cancer as well as determining whether a colon cancer in a subject is stable or progressive by detecting expression levels of a set of 14 biomarkers comprising ADRM1, CDK4, COMT, DHCR7, HMOX2, MCM2, PDXK, POP7, S100P, SNRPA, SORD, STOML2, UMPS and a housekeeping gene.  This recitation is a natural correlation between expression levels of these genes and colon cancer.  With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action.  The claimed invention also recites detecting colon cancer, determining whether the colon cancer is stable or progressive, determining expression levels, normalizing expression levels, comparing scores, using generally recited algorithms, etc which are recitations of abstract ideas because they encompasses mathematical relationships, conclusions and determinations which can occur entirely within the mind or with pencil and paper.  It is therefore determined that the claims are directed to judicial exceptions.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
The claims recite steps of determining gene expression of combinations of genes as well as normalizing and inputting data, however this does not integrate the JE into a practical application because it is mere data gathering and manipulation to use the correlation and does not add a meaningful limitation to the method.  The step of “producing a report” merely provides information as to the results of the method and does not add a meaningful limitation to the method as it simply provides information as to the existence of the natural correlation.  The Supreme Court does acknowledge that it is possible to transform an unpatentable law of nature, but one must do more than simply state the law of nature while adding the words apply it.” CLS BankInt’l, 134 S.Ct. at 2358; Prometheus, 132 S. Cl, at 1294.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
In the instant situation, the step determining gene expression is generally recited and does not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited.  This step is not only a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)).  Applicant is reminded that in Mayo, the Court found that “[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself.  Further conventional or obvious [pre]solution activity is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law”.  Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at ___ (slip op., at 14) (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ . . . adding ‘insignificant post-solution activity’” (quoting Diehr, supra, at 191–192)). The Court also summarized their holding by stating “[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.”  Therefore these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than the determination that a natural correlation/phenomena exists.  Any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
Double Patenting
Claims 1 and 2 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11,414,707. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘707 patent  are coextensive in scope with the instantly pending claims as they are directed to detecting expression of the same genes for colon cancer association determination and treatment.
Claims 32-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11,414,707 in view of US 2017/0233495.  The claims of ‘707 are directed to detecting expression of the same genes as those in the instant claims as well as normalizing and comparing scores, etc.  The claims of the ‘707 are directed to surgical treatment of colon cancer and do not teach the treatments set forth in the instant claims.  However, the claimed treatments were well known in the prior art of cancer treatment (see para 0539 of US 2017/0233495).  Therefore it would have been prima facie obvious to the ordinary artisan prior to the effective filing date to also treat colon cancer patients with the treatments taught by US 2017/0233495 for the obvious benefit of providing effective colon cancer treatment.
Conclusion
No claims are allowed.

APPLICANT REBUTTAL: REMARKS
Upon entry of these amendments, 32-43 are pending. Claims 1 and 2 are canceled herein without prejudice or disclaimer. Applicant reserves the right to pursue the subject matter of the canceled claims in one or more continuation or divisional applications. Amendment and cancellation of certain claims is not to be construed as a dedication to the public of any of the subject matter of the claims as previously presented. No new matter is added.
The Specification has been amended to update the Related Applications paragraph. More specifically, the related Applications paragraph has been updated to include the patent number of USSN 16/253,697 ("the '697 Application") and to update the relationship between the instant application and '697 Application to that of divisional. Applicant submits that such an amendment is proper as the subject matter of the currently pending claims was previously withdrawn by the Office in an Office Action mailed in the '697 Application on September 15, 2021. Applicant further submits an updated Application Data Sheet indicating the change of relationship from continuation to divisional and respectfully requests the issuance of an updated filing receipt reflecting the change of relationship. For the avoidance of doubt, as put forth in MPEP §211.03, a petition under 37 CFR 1.78 is
not
required when changing the relationship between applications when a benefit claim was previously submitted in a timely manner.
Claim Rejections - 35 U.S.C. §101
Claims 1 and 2 are rejected under 35 U.S.C. §101 for allegedly being directed to a natural correlation/law of nature and an abstract idea without significantly more.
Without acquiescing to the validity of the rejection, and solely in an effort to expedite prosecution, claims 1 and 2 are canceled herein without prejudice or disclaimer. Thus, this rejection is moot.
Double Patenting
Claims 1 and 2 are rejected on the ground of nonstatutory double patenting as allegedly being unpatentable over claims 1-9 of U.S. Patent No. 11,414,707 ("the '707 Patent"). Applicant respectfully disagrees.
Without acquiescing to the validity of the rejection, and solely in an effort to expedite prosecution, claims 1 and 2 are canceled herein without prejudice or disclaimer. Thus, this rejection is moot.
Claims 32-43 are rejected on the ground of nonstatutory double patenting as being
unpatentable over claims 1-9 of the '707 Patent in view of U.S. Publication No. 2017/0233495. Applicant respectfully disagrees.
As described supra, the instant application is a proper divisional of the '697 Application (corresponding to the '707 Patent), as the instant claims are directed to subject matter that was withdrawn by the Office during the prosecution of the '697 Application. Accordingly, pursuant to 35 U.S.C. §121, and as described in MPEP §804.01, this nonstatutory double patenting rejection is improper and should be withdrawn.
CONCLUSION

NEXT OFFICE ACTION: ALLOWANCE
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 .
An updated filing receipt was issued 1/15/2025.  The instant application is a Divisional application of 16/253,697.
The rejection under Obviousness type Double Patenting, made in the previous office action dated 6/6/2024, is withdrawn.
Claims 32-43 are allowed.

CITED REFERENCE SUMMARIES: Ref US20170233495A1: Claims:
- 25 . (canceled)
An isolated antibody specific for MMP9 or an antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment thereof binds to MMP9 by interacting with an epitope comprising at least one amino acid within a region consisting of SEQ ID NO: 41, at least one amino acid within a region consisting of SEQ ID NO: 42, and at least one amino acid within a region consisting of SEQ ID NO: 43, wherein said regions are within the catalytic domain of human MMP9.
The isolated antibody or antigen-binding fragment according to claim 26 comprising a heavy chain variable region comprising: (i) a heavy chain CDR1 of SEQ ID NO: 2 or a variant thereof wherein 1, 2, or 3 amino acids of said heavy chain CDR1 is substituted by a different amino acid; (ii) a heavy chain CDR2 of SEQ ID NO: 3 or a variant thereof wherein 1, 2, or 3 amino acids of said heavy chain CDR2 is substituted by a different amino acid; and (iii) a heavy chain CDR3 of SEQ ID NO: 4 or a variant thereof wherein 1, 2, or 3 amino acids of said heavy chain CDR3 is substituted by a different amino acid.
(i) a heavy chain CDR1 of SEQ ID NO: 2 or a variant thereof wherein 1, 2, or 3 amino acids of said heavy chain CDR1 is substituted by a different amino acid;
(ii) a heavy chain CDR2 of SEQ ID NO: 3 or a variant thereof wherein 1, 2, or 3 amino acids of said heavy chain CDR2 is substituted by a different amino acid; and
(iii) a heavy chain CDR3 of SEQ ID NO: 4 or a variant thereof wherein 1, 2, or 3 amino acids of said heavy chain CDR3 is substituted by a different amino acid.
The isolated antibody or antigen-binding fragment according to claim 27 , wherein the heavy chain variable region comprises SEQ ID NO: 11, or a variant thereof wherein 1, 2, or 3 amino acids of at least one of the heavy chain CDR1, CDR2, and/or CDR3, and/or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids of the heavy chain variable framework region is substituted by a different amino acid.
The isolated antibody or antigen-binding fragment according to claim 27 , wherein said heavy chain variable region comprises an amino acid sequence selected from: (i) the amino acid sequence SEQ ID NO: 12; (ii) the amino acid sequence SEQ ID NO: 13; (iii) the amino acid sequence SEQ ID NO: 14; (iv) the amino acid sequence SEQ ID NO: 15; (v) the amino acid sequence SEQ ID NO: 16; (vi) the amino acid sequence SEQ ID NO: 17; (vii) the amino acid sequence SEQ ID NO: 18; (viii) the amino acid sequence SEQ ID NO: 19; (ix) the amino acid sequence SEQ ID NO: 20; or (x) the amino acid sequence of SEQ ID NO: 11.
(i) the amino acid sequence SEQ ID NO: 12;
(ii) the amino acid sequence SEQ ID NO: 13;
(iii) the amino acid sequence SEQ ID NO: 14;
(iv) the amino acid sequence SEQ ID NO: 15;
(v) the amino acid sequence SEQ ID NO: 16;
(vi) the amino acid sequence SEQ ID NO: 17;
(vii) the amino acid sequence SEQ ID NO: 18;
(viii) the amino acid sequence SEQ ID NO: 19;
(ix) the amino acid sequence SEQ ID NO: 20; or
(x) the amino acid sequence of SEQ ID NO: 11.
The isolated antibody or antigen-binding fragment according to claim 27 , further comprising a light chain variable region selected from: a) a light chain variable region comprising: (i) a light chain CDR1 of SEQ ID NO: 21 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR1 is substituted by a different amino acid; (ii) a light chain CDR2 of SEQ ID NO: 22 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR2 is substituted by a different amino acid; and (iii) a light chain CDR3 of SEQ ID NO: 23 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR3 is substituted by a different amino acid, or b) a light chain variable region comprising: (i) a light chain CDR1 of SEQ ID NO: 26 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR1 is substituted by a different amino acid; (ii) a light chain CDR2 of SEQ ID NO: 27 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR2 is substituted by a different amino acid; and (iii) a light chain CDR3 of SEQ ID NO: 28 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR3 is substituted by a different amino acid.
a) a light chain variable region comprising: (i) a light chain CDR1 of SEQ ID NO: 21 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR1 is substituted by a different amino acid; (ii) a light chain CDR2 of SEQ ID NO: 22 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR2 is substituted by a different amino acid; and (iii) a light chain CDR3 of SEQ ID NO: 23 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR3 is substituted by a different amino acid, or
(i) a light chain CDR1 of SEQ ID NO: 21 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR1 is substituted by a different amino acid;
(ii) a light chain CDR2 of SEQ ID NO: 22 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR2 is substituted by a different amino acid; and
(iii) a light chain CDR3 of SEQ ID NO: 23 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR3 is substituted by a different amino acid, or
b) a light chain variable region comprising: (i) a light chain CDR1 of SEQ ID NO: 26 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR1 is substituted by a different amino acid; (ii) a light chain CDR2 of SEQ ID NO: 27 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR2 is substituted by a different amino acid; and (iii) a light chain CDR3 of SEQ ID NO: 28 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR3 is substituted by a different amino acid.
(i) a light chain CDR1 of SEQ ID NO: 26 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR1 is substituted by a different amino acid;
(ii) a light chain CDR2 of SEQ ID NO: 27 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR2 is substituted by a different amino acid; and
(iii) a light chain CDR3 of SEQ ID NO: 28 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR3 is substituted by a different amino acid.
The isolated antibody or antigen-binding fragment according to claim 30 , wherein the light chain variable region comprises an amino acid sequence selected from: (1) SEQ ID NO: 24, or a variant thereof wherein 1, 2, or 3 amino acids of at least one of the light chain CDR1, CDR2, and/or CDR3, and/or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids of the light chain variable framework region is substituted by a different amino acid, or (2) SEQ ID NO: 29, or a variant thereof wherein 1, 2, or 3 amino acids of at least one of the light chain CDR1, CDR2, and/or CDR3, and/or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids of the light chain variable framework region is substituted by a different amino acid.
(1) SEQ ID NO: 24, or a variant thereof wherein 1, 2, or 3 amino acids of at least one of the light chain CDR1, CDR2, and/or CDR3, and/or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids of the light chain variable framework region is substituted by a different amino acid, or
(2) SEQ ID NO: 29, or a variant thereof wherein 1, 2, or 3 amino acids of at least one of the light chain CDR1, CDR2, and/or CDR3, and/or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids of the light chain variable framework region is substituted by a different amino acid.
The isolated antibody or antigen-binding fragment according to claim 30 , wherein the light chain variable region comprises an amino acid sequence selected from: (i) the amino acid sequence of SEQ ID NO: 67; (ii) the amino acid sequence of SEQ ID NO: 68; (iii) the amino acid sequence of SEQ ID NO: 69; or (iv) the amino acid sequence of SEQ ID NO: 70.
(i) the amino acid sequence of SEQ ID NO: 67;
(ii) the amino acid sequence of SEQ ID NO: 68;
(iii) the amino acid sequence of SEQ ID NO: 69; or
(iv) the amino acid sequence of SEQ ID NO: 70.
The isolated antibody or antigen-binding fragment according to claim 26 , which inhibits the catalytic activity of MMP9.
The isolated antibody according to claim 26 , which is a human monoclonal antibody.
The isolated antibody according to claim 26 , wherein said antibody comprises a heavy chain variable region of SEQ ID NO: 19 and a light chain variable region of SEQ ID NO: 70.
An isolated nucleic acid molecule encoding an antibody or antigen binding fragment according to claim 26 .
The isolated nucleic acid according to claim 36 comprising one or more of: (1) a nucleic acid sequence comprising SEQ ID NO: 31, SEQ ID NO: 32, and SEQ ID NO: 33, or a variant thereof having at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with one of said sequences, and/or (2) a nucleic acid sequence selected from: a) a nucleic acid sequence comprising SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 36, or a variant thereof having at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with one of said sequences, or b) a nucleic acid sequence comprising SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, or a variant thereof having at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with one of said sequences.
(1) a nucleic acid sequence comprising SEQ ID NO: 31, SEQ ID NO: 32, and SEQ ID NO: 33, or a variant thereof having at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with one of said sequences, and/or
(2) a nucleic acid sequence selected from: a) a nucleic acid sequence comprising SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 36, or a variant thereof having at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with one of said sequences, or b) a nucleic acid sequence comprising SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, or a variant thereof having at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with one of said sequences.
a) a nucleic acid sequence comprising SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 36, or a variant thereof having at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with one of said sequences, or
b) a nucleic acid sequence comprising SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, or a variant thereof having at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with one of said sequences.
A recombinant expression vector comprising a nucleic acid molecule according to claim 36 .
A host cell comprising a recombinant vector according to claim 38 .
A process for producing antibodies or antigen-binding fragments according to claim 26 comprising culturing a host cell transformed with an expression vector comprising a nucleic acid sequence that encodes said antibodies or antigen-binding fragments under conditions sufficient to promote expression of said antibodies or said antigen-binding fragments.
A pharmaceutical composition comprising one or more of (i) an antibody specific for MMP9 or antigen binding fragment thereof according to claim 26 , (ii) a nucleic acid encoding said antibody or antigen binding fragment, (iii) a recombinant expression vector comprising a nucleic acid encoding said antibody or antigen binding fragment, and/or (iv) a host cell comprising a recombinant expression vector comprising a nucleic acid encoding said antibody or antigen binding fragment and at least one pharmaceutically acceptable carrier.
An ex-vivo method for detecting the presence and/or concentration of MMP9 protein in a biological sample, comprising the steps of: (i) providing a biological sample from a subject, (ii) reacting said biological sample with at least one antibody or antigen-binding fragment according to claim 26 , under conditions sufficient for binding MMP9 protein present in said biological sample to said at least one antibody or antigen binding fragment through antigen-antibody interactions; and (iii) detecting a signal proportional to the level of antigen-antibody complex foil led in step (ii), wherein the intensity of the signal correlates with the concentration of MMP9 protein in the biological sample.
(i) providing a biological sample from a subject,
(ii) reacting said biological sample with at least one antibody or antigen-binding fragment according to claim 26 , under conditions sufficient for binding MMP9 protein present in said biological sample to said at least one antibody or antigen binding fragment through antigen-antibody interactions; and
(iii) detecting a signal proportional to the level of antigen-antibody complex foil led in step (ii),
wherein the intensity of the signal correlates with the concentration of MMP9 protein in the biological sample.
The ex-vivo method according to claim 42 for detecting the presence and/or concentration of active MMP9 protein in a biological sample.
The ex-vivo method according to claim 42 , wherein at least one antibody or antigen binding fragment thereof comprises a heavy chain variable region of SEQ ID NO: 19 and a light chain variable region of SEQ ID NO: 70.
A method for preventing and/or treating a MMP9-related disease in a subject in need thereof comprising administering an antibody according to claim 26 to said subject.
The method according to claim 45 , wherein the a MMP9-related disease is selected from inflammatory and autoimmune diseases, inflammatory bowel diseases, cancers or tumors, fibrotic diseases, cardiovascular diseases, neurological disorders, or eye diseases.
The method according to claim 45 , wherein an antibody comprises a heavy chain variable region of SEQ ID NO: 19 and a light chain variable region of SEQ ID NO: 70.
Ref US11414707: Claims:
1. A method of treating colon cancer in a subject comprising:
determining the expression level of at least 14 biomarkers from a test sample from a subject by contacting the test sample with a plurality of agents specific to detect the expression of the at least 14 biomarkers, wherein the 14 biomarkers comprise ADRM1, CDK4, COMT, DHCR7, HMOX2, MCM2, PDXK, POP7, S100P, SNRPA, SORD, STOML2, UMPS, and a housekeeping gene, wherein the housekeeping gene is MORF4L1;
normalizing the expression level of each of ADRM1, CDK4, COMT, DHCR7, HMOX2, MCM2, PDXK, POP7, S100P, SNRPA, SORD, STOML2, and UMPS to the expression level of the housekeeping gene, thereby obtaining a normalized expression level of each of ADRM1, CDK4, COMT, DHCR7, HMOX2, MCM2, PDXK, POP7, S100P, SNRPA, SORD, STOML2, and UMPS;
inputting each normalized expression level into an algorithm to generate a score, wherein the algorithm is a product of a model of colon cancer disease derived using the XGB algorithm;
comparing the score with a predetermined cutoff value; and
determining that the score is equal to or greater than the predetermined cutoff value, thereby identifying the subject as having colon cancer; and
administering to the subject identified as having colon cancer a therapy, wherein the therapy comprises surgery.
2. The method of claim 1, wherein the predetermined cutoff value is at least 50% on a scale of 0-100%.
3. The method of claim 1, wherein the predetermined cutoff value is at least 60% on a scale of 0-100%.
4. The method of claim 1, wherein the predetermined cutoff value has a sensitivity of identifying the subject as having colon cancer that is greater than 85%.
5. The method of claim 1, wherein the predetermined cutoff value has a specificity of identifying the subject as having colon cancer that is greater than 75%.
6. The method of claim 1, wherein at least one of the at least 14 biomarkers is RNA, cDNA or protein.
7. The method of claim 6, wherein when the biomarker is RNA, the RNA is reverse transcribed to produce cDNA, and the produced cDNA expression level is detected.
8. The method of claim 1, wherein the predetermined cutoff value is derived from a plurality of reference samples obtained from subjects not having or not diagnosed with a colon cancer.
9. The method of claim 1, wherein the surgery comprises removing a polyp during a colonoscopy, endoscopic mucosal resection, a partial colectomy, an ostomy, removing at least one cancerous lesion from the liver, or any combination thereof.
Ref US20170233495: Claims:
1-25. (canceled)
26. An isolated antibody specific for MMP9 or an antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment thereof binds to MMP9 by interacting with an epitope comprising at least one amino acid within a region consisting of SEQ ID NO: 41, at least one amino acid within a region consisting of SEQ ID NO: 42, and at least one amino acid within a region consisting of SEQ ID NO: 43, wherein said regions are within the catalytic domain of human MMP9.
27. The isolated antibody or antigen-binding fragment according to claim 26 comprising a heavy chain variable region comprising:
(i) a heavy chain CDR1 of SEQ ID NO: 2 or a variant thereof wherein 1, 2, or 3 amino acids of said heavy chain CDR1 is substituted by a different amino acid;
(ii) a heavy chain CDR2 of SEQ ID NO: 3 or a variant thereof wherein 1, 2, or 3 amino acids of said heavy chain CDR2 is substituted by a different amino acid; and
(iii) a heavy chain CDR3 of SEQ ID NO: 4 or a variant thereof wherein 1, 2, or 3 amino acids of said heavy chain CDR3 is substituted by a different amino acid.
28. The isolated antibody or antigen-binding fragment according to claim 27, wherein the heavy chain variable region comprises SEQ ID NO: 11, or a variant thereof wherein 1, 2, or 3 amino acids of at least one of the heavy chain CDR1, CDR2, and/or CDR3, and/or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids of the heavy chain variable framework region is substituted by a different amino acid.
29. The isolated antibody or antigen-binding fragment according to claim 27, wherein said heavy chain variable region comprises an amino acid sequence selected from:
(i) the amino acid sequence SEQ ID NO: 12; (ii) the amino acid sequence SEQ ID NO: 13; (iii) the amino acid sequence SEQ ID NO: 14; (iv) the amino acid sequence SEQ ID NO: 15; (v) the amino acid sequence SEQ ID NO: 16; (vi) the amino acid sequence SEQ ID NO: 17; (vii) the amino acid sequence SEQ ID NO: 18; (viii) the amino acid sequence SEQ ID NO: 19; (ix) the amino acid sequence SEQ ID NO: 20; or (x) the amino acid sequence of SEQ ID NO: 11.
30. The isolated antibody or antigen-binding fragment according to claim 27, further comprising a light chain variable region selected from:
a) a light chain variable region comprising:
(i) a light chain CDR1 of SEQ ID NO: 21 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR1 is substituted by a different amino acid;
(ii) a light chain CDR2 of SEQ ID NO: 22 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR2 is substituted by a different amino acid; and
(iii) a light chain CDR3 of SEQ ID NO: 23 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR3 is substituted by a different amino acid, or
 b) a light chain variable region comprising:
(i) a light chain CDR1 of SEQ ID NO: 26 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR1 is substituted by a different amino acid;
(ii) a light chain CDR2 of SEQ ID NO: 27 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR2 is substituted by a different amino acid; and
(iii) a light chain CDR3 of SEQ ID NO: 28 or a variant thereof wherein 1, 2, or 3 amino acids of said light chain CDR3 is substituted by a different amino ac
[Truncated to input limit]