Office Action 1: Non-Final Rejection (2024-09-17)
Rejection types: 103 - Obviousness, 112 - Written Description/Enablement

CLAIMS:
WHAT IS CLAIMED IS:

1\. An antibody comprising an antigen recognition region which binds a catalytic site of MMP-7, having complementarity determining region (CDR) amino acid sequences as set forth in: SEQ ID NOs: 3 (CDR1), 4 (CDR2) and 5 (CDR3), sequentially arranged from N to C on a light chain of the antibody; and SEQ ID NOs: 6 (CDR1), 7 (CDR2) and 8 (CDR3), sequentially arranged from N to C on a heavy chain of the antibody.

2\. The antibody of claim 1, having a VL amino acid sequence as set forth in SEQ ID NO: 1.

3\. The antibody of claim 1, having a VH amino acid sequence as set forth in SEQ ID NO: 2.

4\. The antibody of any of claims 1-3 attached to a detectable moiety or a therapeutic moiety.

5\. A method of treating a disease associated with imbalanced or abnormal activity of MMP-7 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the antibody of claim 1, thereby treating the disease associate with imbalanced or abnormal activity of MMP-7 in the subject.

6\. The method of claim 5, wherein the disease is cancer.

7\. The method of claim 6, wherein the cancer is pancreatic cancer.

8\. A method of diagnosing a disease associated with imbalanced or abnormal activity of MMP-7 in a subject, the method comprising contacting a sample of the subject with the antibody of claim 1 so as to analyze expression of MMP-7, wherein an upregulation of expression of said MMP-7 is indicative of the disease associated with imbalanced or abnormal activity of MMP-7.

9\. The method of claim 8, wherein the disease is cancer.

10\. The method of claim 9, wherein the cancer is pancreatic cancer.

11\. A method of treating cancer in a subject in need thereof comprising:
(a) analyzing in a sample of the subject for an amount of MMP-7; and
(b) administering to the subject a therapeutically effective amount of the antibody of any one of claims
1-3 upon confirmation that said amount of said MMP-7 is above a predetermined level, thereby treating the cancer.

12\. A method of treating cancer in a subject in need thereof comprising:
(a) analyzing in a sample of the subject for an amount of MMP-7 using the antibody of any one of claims
1-3; and
(b) administering to the subject a therapeutically effective amount of an agent which down-regulates the amount of said MMP-7 upon confirmation that said amount of said MMP-7 is above a predetermined level, thereby treating the cancer.

13\. The method of claim 11, wherein said analyzing is effected using an antibody.

14\. The method of claim 13, wherein said antibody is the antibody of any one of claims 1-3.

15\. A method of treating pancreatic cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an antibody comprising an antigen recognition region which binds a catalytic site of MMP-7, wherein the antibody inhibits the activity of said MMP-7 and wherein the Ki of the antibody towards said MMP-7 is at least 5 times lower than a Ki of the antibody towards MMP2 or MMP9, thereby treating the pancreatic cancer.

16\. The method of claim 15, wherein the antibody is the antibody of any one of claims 1-3.

17\. The method of claims 15 or 16 further comprising administering to the subject a chemotherapeutic agent.

18\. The method of claim 17, wherein said chemotherapeutic agent is a nucleoside analogue.

19\. The method of claim 18, wherein said nucleotide analogue comprises gemcitabine.

20\. The method of claim 17, wherein said chemotherapeutic agent is Oxaliplatin.

21\. The method of claim 17, wherein the dose of said chemotherapeutic agent is less than the gold standard dose when used as a single agent.

22\. A pharmaceutical composition comprising the antibody of any one of the claims 1-4.

23\. An article of manufacture comprising the antibody of any one of claims 1-4 and a chemotherapeutic agent.

24\. The article of manufacture of claim 23, wherein said chemotherapeutic agent is a nucleoside analogue.

25\. The article of manufacture of claim 24, wherein said nucleotide analogue comprises gemcitabine.

26\. The article of manufacture of claim 23, wherein said chemotherapeutic agent is Oxaliplatin.

27\. The article of manufacture of claim 23, wherein said antibody and said chemotherapeutic agent are formulated in a single composition.

28\. An isolated polynucleotide encoding at least one CDR amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 4, 5, 6, 7 and 8.

29\. The isolated polynucleotide of claim 28, encoding the CDR amino acid sequence as set forth in SEQ ID NOs: 3-5.

30\. The isolated polynucleotide of claim 28, encoding the CDR amino acid sequence as set forth in SEQ ID NOs: 6-8.

31\. The isolated polynucleotide of claim 28, encoding the CDR amino acid sequence as set forth in SEQ ID NOs: 3-8.

32\. The antibody of any one of claims 1-3, for use in treating cancer.

33\. The antibody of claim 32, wherein the cancer is pancreatic cancer.

34\. The article of manufacture of any one of claims 23-27, for use in treating cancer.

35\. The article of manufacture of claim 34, wherein said cancer is pancreatic cancer.

OFFICE 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 .
DETAILED ACTION
Claims 5-7, 11-13, 15-21, and 23-27 are currently pending and are examined on the merits.
Information Disclosure Statement
The information disclosure statements filed on 10/06/2021, 08/14/2023, 08/20/2023, 01/30/2024, and 03/17/2024 are acknowledged and have been considered.
The listing of references in the specification is not a proper information disclosure statement.  37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, the list may not be incorporated into the specification but must be submitted in a separate paper.  Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to for the following reasons:
The description in the specification of Fig. 4C relates to protein levels of FasL in cells treated with GSM-192, but the first panel of Fig. 4C drawing relates to apoptotic cells, described under Fig. 4B in the specification. (Pg. 5, lines 24-34)
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
As a reminder to applicants, the abstract should be in narrative form and generally limited to a single paragraph preferably within the range of 50 to 150 words in length. The abstract should not exceed 15 lines of text. Abstracts exceeding 15 lines of text or 150 words should be checked to see that they are as concise as the disclosure permits. The form and legal phraseology often used in patent claims, such as means and said, should be avoided. The abstract should sufficiently describe the disclosure to assist readers in deciding whether there is a need for consulting the full patent text for details.
The abstract of the disclosure is objected to because it is not in narrative form and does not effectively summarize the invention as claimed.  The abstract is a single incomplete sentence drawn to an antibody required by most claims, but the claims are drawn to methods of using or compositions comprising said antibody. The antibody as a product is not itself claimed. Correction is required.  See MPEP § 608.01(b).
Claim Rejections - 35 USC § 112(b)
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.
Claims 5-7, 11-13, 16, and 23-27 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.
With regard to Claims 5-7, 11-13, 16, and 23-27, the terms in parentheses as recited in Claims 5, 11-12, 16, and 23 – for example “(CDR1)” – function as “exemplary language”. Claims containing exemplary language are rendered indefinite because it is unclear whether the limitations within the parentheses are part of the claimed invention. See MPEP § 2173.05(d). This rejection can be overcome by amending Claims 5, 11-12, 16, and 23 to remove the terms in parentheses.
Claims 5-7, 11-13, 16, and 23-27 are further rejected under 35 U.S.C. 112(b) for requiring the limitation of an antibody “which binds a catalytic site of MMP-7”, as recited in Claims 5, 11-12, 16, and 23.  MMPs are generally understood to have an “active site”, sometimes called a “catalytic cleft”, within a larger “catalytic domain”.  The active site further comprises three conserved histidine residues and a catalytic Zn2+ responsible for its enzymatic activity.  In the art, the term “catalytic site” generally refers to a subset of the active site and is defined by the residues directly responsible for catalysis (Porter 2004, DOI: 10.1093/nar/gkh028; Introduction).  The instant specification does not directly define “catalytic site”, but does make use of the term relative to “haptens which mimic the metal-bound catalytic site” (Pg. 8, line 32).  A minimal “Zn tripod” hapten was utilized as an immunogen to generate the disclosed antibody (Fig. 2E), and such a hapten was described previously as “able to mimic the three-dimensional structure of the respective zinc-histidine epitope in the native protein” (Sagi 2008, WO2008102359).  Given that the only similarity between the Zn tripod hapten and MMP-7 is a Zn2+ ion bound to three imidazole rings (mimicking the side chains of histidine residues), the term “catalytic site” is interpreted to include only the Zn+2 ion and the coordinating histidine residues – which is in general agreement with the use of the term in the art.
The structure of an antibody comprising the light and heavy chain CDRs of SEQ ID NOs: 3-8 and represented as “GSM-192” (Pg. 36, line 30 – Pg. 37 line 4) was determined by protein crystallography, and its predicted interaction with activated human MMP-7 was computationally modelled (Fig. 3).  Notably, the model predicts GSM-192 to bind “exosites” (Pg. 6, lines 12, 16) “close to the conserved active site” (Pg. 6, line 9) of MMP-7, rather than the catalytic site itself.  Additionally, the catalytic site remains accessible to the small molecule inhibitor acetohydroxamic acid (AHA) (leaving “a small tunnel through which the small inhibitor AHA can insert at the interface and bind to the Zn2+ ion”; Pg. 6, lines 18-20).  Further, structures modelled without AHA showed that its binding site was “empty and accessible” (Pg. 39, line 21-23).
While it is clear from the disclosure that that an antibody comprising the CDRs of SEQ ID NOs: 3-8 is capable of blocking MMP-7 enzymatic activity (Fig. 2D; Pg. 6, lines 1-2), evidence presented in the docking model, including the simultaneous binding of AHA, reveal that the antibody as claimed does not, in fact, bind the “catalytic site of MMP-7” directly.  Therefore, an antibody comprising the SEQ ID NOs Of 3-8 does not bind to the “catalytic site of MMP-7” as required by the claim.  Therefore, the metes and bounds of claims 5, 11-12, 16, and 23 are unclear.
Claim Rejections - 35 USC § 112(a)
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 15 and 17-21 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 claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention.  This is a written description rejection.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or it may be satisfied by the disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.  “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.  Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
Scope of the claimed antibodies and description in the specification.
Claims 15 and 17-21 are drawn to a genus of antibody “which binds a catalytic site of MMP-7” and is not limited by any particular sequence. The antibody of Claim 15 is, however, further limited by its function relative to MMP-7, “wherein the antibody inhibits the activity of said MMP-7 and wherein the Ki of the antibody towards said MMP-7 is at least 5 times lower than a Ki of the antibody towards MMP2 or MMP9”. Claim 16, which depends from Claim 15, is further limited by a set of specific CDR sequences, specifically a light chain comprising SEQ ID NOs: 3, 4, and 5 and a heavy chain comprising SEQ ID NOs: 6, 7, and 8, and is therefore not included in this rejection.
The instant specification details a single species of MMP-7-binding antibody named “GSM-192” comprising a light chain defined by SEQ ID NO: 1 (which comprises the CDRs of SEQ ID NOs: 3, 4, and 5) and a heavy chain defined by SEQ ID NO: 2 (which comprises the CDRs of SEQ ID NOs: 6, 7, and 8) (Pg. 36, line 30 – Pg. 37 line 4). A crystal structure of GSM-192 was determined, computational modelling of GSM-192 in complex with MMP-7 is disclosed (Figure 3), and applicants highlight several residues computationally predicted to be involved in “hydrophobic anchoring” of the antibody to MMP-7 (Pg. 44, lines 14-21).
Functionally, GSM-192 is demonstrated to bind MMP-7 “close to the conserved active site” (Pg. 6, line 9) and to inhibit its enzymatic activity (Pg. 6, line 1), but does not display substantial inhibition of “related MMP’s such as MMP-14, -9, and -12” (Pg. 6, line 2-3; Fig. 2D). GSM-192 was shown to have poor binding affinity for MMP-9, -12, -13, and -14 (Pg. 5, lines 33-34; Fig. 2C).
State of the relevant art
Matrix Metalloproteinase 7 (MMP-7) has long been considered a potential target for cancer therapies, and Mitsiades 2001 (PMID: 11212252) posits that “specific inhibition of MMP7 may provide a potentially effective approach toward increasing the efficacy of chemotherapy”. Although previous studies explore the use of MMP inhibitors in treating cancer, including pancreatic cancer, all members of the MMP family share a highly conserved catalytic site, and first-generation MMP inhibitors display poor selectivity between MMP species – causing significant toxicity in clinical trials (Winer 2018, DOI: 10.1158/1535-7163.MCT-17-0646). More recent efforts have focused on developing inhibitors and antibodies that target “exosites” outside the conserved catalytic cleft in order to confer specificity (Sagi 2017; DOI: 10.1016/j.bbamcr.2017.06.009).  Sagi 2013 (US 2013/0209491 A1) discloses an inhibitory MMP-7 antibody and a method for generating antibodies that inhibit MMPs by sequential immunization with a “synthetic Zn-mimicry epitope” followed by an MMP antigen. Older iterations of this method using only the Zn-mimicry epitope for immunization have resulted in a highly selective antibody against related MMP-9 that showed “therapeutic potential” (Sela-Passwell 2012; DOI: 10.1038/nm.2582).  The antibodies of Sagi that inhibit MMP-7 activity are conventional antibodies with 6 distinct CDR sequences.
Are the disclosed species representative of the claimed genus?
MPEP § 2163 states that a “representative number of species” means that the species that are adequately described are representative of the entire genus.  Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
As summarized above, the specification discloses a single species of MMP-7 antibody.  Claim 15 does not include the sequence of the disclosed species among its limitations but instead specifies the structure of an MMP-7 antibody through its particular ability to selectively bind and inhibit MMP-7, “wherein the Ki of the antibody towards said MMP-7 is at least 5 times lower than a Ki of the antibody towards MMP2 or MMP9”. The instant disclosure makes clear “the antibody may bind to the metal-coordinating ions of the catalytic site and not the metal ion itself” (Pg. 15, lines 21-22) and further states: “It will be appreciated that the antibody may, in addition to binding to the catalytic site, bind to sites on the surface of MMP-7” (Pg. 15, lines 22-23).  Therefore, the antibody disclosed (GSM-192) is but one of many possible antibodies covered by Claims 15 and 17-21, each likely comprising unique sequences and affinities for epitopes not anticipated by the instant disclosure.
Sela-Culang 2013 (DOI: 10.3389/fimmu.2013.00302) teaches that antigens typically lack “intrinsic properties that clearly differentiate between epitopic and non-epitopic residues” and “most of the [antigen] surface may become a part of an epitope under some circumstances”. As such, and without evidence to the contrary, the genus as claimed is of substantial breadth and would potentially encompass any antibody that binds to any set of residues in and around the active site of MMP-7, provided it has a Ki at least 5 times lower than the Ki towards MMP2 or MMP9. Because an antibody need not bind the same epitope as GSM-192 in order to satisfy the claimed functionality, GSM-192 alone cannot reasonably be representative of all possible species in the claimed genus. Further, it is well accepted in the arts that a disclosure of an epitope does not permit a skilled artisan to predict all the antibodies that binds to the epitope.  Thus, disclosure of GSM 192 does not permit a skilled artisan to visualize the genus of antibodies that binds to MMP-7 with a Ki that is 5 times lower than the Ki for MMP-2 or MMP-9 as required by the instant claims.
Identifying characteristics and structure-function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.  To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed binding activity.
In the instant case, the structural features necessary for an antibody to “bind” or “inhibit” MMP-7 must be sufficiently detailed. Further, Claims 15-21 require the limitation “wherein the Ki of the antibody towards said MMP-7 is at least 5 times lower than a Ki of the antibody towards MMP2 or MMP9”.
Dondelinger 2018 (DOI: 10.3389/fimmu.2018.02278) discusses the complex relationship between binding affinities and antigen selectivity: “It should be noted that: (i) some contacting residues may contribute minimally to the binding free energy and even disfavor the complex formation and; (ii) that a residue energetically important for binding to the cognate antigen may not be important for the difference in affinity between cognate and non-cognate antigens and, finally; (iii) a residue crucial for antigen recognition may not be important for binding free energy.” Although Figs. 2C-2D show compelling evidence that GSM-192 possesses poor binding affinity and inhibition activity towards other “related” MMPs, such as MMP-9 and MMP-14, and computational modeling predicts several interacting residues between the CDRs and MMP-7, the particular features of GSM-192 that confer the specificity towards MMP-7 to the exclusion of similar MMPs are not disclosed, neither are any other representative species capable of this level of discrimination. Furthermore, no data regarding MMP-2 is presented relative to GSM-192 or any other species of MMP-7 antibody, and it is unclear from the specification that the single disclosed species satisfies this limitation.
Dondelinger 2018 further states: “Importantly, many residues included within the CDRs are not directly in contact with the antigen, but may also play an important role in the Ag-Ab interaction by upholding the optimal conformation and orientation of nearby interacting residue.” The disclosure highlights several residues on GSM-192 predicted to interface directly with the surface of MMP-7 (Figure 3), however the influence of residues adjacent to these positions is not discussed. The disclosure provides no evidence that these contacting residues are sufficient to confer the necessary affinity and specificity for MMP-7, nor are any modifications made to the disclosed sequence to test the necessity and/or contribution of the non-contacting residues to the claimed function. As currently presented, the disclosure only contains sufficient detail to support the function of the particular combination of light and heavy chains comprising the CDRs as recited in Claims 5, 11-12, 16, and 23. Therefore one of ordinary skill in the art would be unable to determine if applicants were in possession of the full scope of the invention as set forth in Claims 15 and 17-21.
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.
Claims 5-7, 11-13, and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Sagi 2013 (US 2013/0209491 A1), herein “Sagi”, and further in view of Dym 2019 (https://doi.org/10.2210/pdb6FBJ/pdb; published January 30, 2019 ), herein “Dym”, and Fukuda 2011, (DOI: 10.1016/j.ccr.2011.03.002) herein “Fukuda”.
Sagi teaches an antibody “comprising an antigen recognition region which binds a catalytic site of MMP-7, wherein the antibody inhibits the activity of the MMP-7 and wherein the Ki of the antibody towards the MMP-7 is at least 5 times lower than a Ki of the antibody towards MMP2 or MMP9.” (Pg. 1, Par. 0011)
Sagi further teaches “a method of treating a disease associated with imbalanced or abnormal activity of MMP-7 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the antibody against MMP-7, thereby treating the disease associate with imbalanced or abnormal activity of MMP-7 in the subject.” (Pg. 1-2, Par. 0020)
Sagi further teaches a “method of diagnosing a disease associated with imbalanced or abnormal activity of MMP-7 in a subject, the method comprising contacting a sample of the subject with the antibody of the present invention so as to analyze expression of MMP-7, wherein an upregulation of expression of the MMP-7 is indicative of the disease associated with imbalanced or abnormal activity of MMP-7.” (Pg. 2, Par. 0021)
Sagi further teaches “the disease is cancer”. (Pg. 2, Par. 0050)
Sagi does not teach that the disease can be pancreatic cancer, nor that the MMP-7 antibody comprises CDRs comprising SEQ ID NOs: 3-8.  However, these deficiencies are cured by Dym and Fukuda.
Dym teaches 6FBJ, a monoclonal antibody targeting MMP-7 (Title) that is the same as the MMP-7 antibody of the instant disclosure (“GSM-192 Fab have been deposited in the PDB under the ID code 6FBJ.”; Pg. 37, line 26) comprising instant SEQ ID NOs: 3-5 sequentially arranged from N to C on its light chain and instant SEQ ID NOs: 6-8 sequentially arranged from N to C on its heavy chain (See sequence: https://www.rcsb.org/fasta/entry/6FBJ/display).
Fukuda teaches that knockout of MMP-7 in a pancreatic ductal adenocarcinoma (PDA) mouse model limits tumor size and metastasis (Fig. 6; Abstract). Fukuda further demonstrates that “serum MMP7 level in human patients with PDA correlated with metastatic disease and survival”, wherein lower serum levels correlated with higher survival (Abstract; Fig. 7).
One of ordinary skill in the art would be motivated to modify the methods of treating and diagnosing a disease taught by Sagi, to use the 6FBJ MMP-7 taught by Dym and to include pancreatic cancer as the target disease, according to the teachings of Fukuda.  Sagi teaches a method of diagnosing comprising detecting MMP-7 protein levels, and treating cancer with an MMP-7 antibody; Dym teaches an MMP-7 specific antibody; and Fukuda teaches that MMP-7 knockout in pancreatic ductal adenocarcinoma reduces tumor burden and high MMP-7 levels correlate with a poor prognosis.  Given what is known in the art, one would reasonably expect that inhibiting MMP-7 with the 6FBJ MMP-7 antibody would result in decreased tumor size, fewer metastases, and higher survival in a pancreatic cancer patient.
Claims 17, 20, 23, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Sagi 2013 (US 2013/0209491 A1), herein “Sagi”, Dym 2019 (https://doi.org/10.2210/pdb6FBJ/pdb; published January 30, 2019), herein “Dym”, and Fukuda 2011, (DOI: 10.1016/j.ccr.2011.03.002) herein “Fukuda” as applied to claims 5-7, 11-13, and 15-16 above, and further in view of Almendro 2009 (DOI: 10.1371/journal.pone.0004728), herein “Almendro”.
The teachings of Sagi, Dym, and Fukuda are described above.
Together Sagi, Dym, and Fukuda do not teach combining MMP7-inhibition with a chemotherapeutic agent.  However, this deficiency is cured by Almendro.
Almendro teaches that MMP-7 contributes to chemoresistance of cancer cells through its interaction with the Fas/FasL pathway (Abstract; Fig. 8) and that inhibition of MMP-7 augments the ability of chemotherapeutic agent oxaliplatin to induce cell death in cancer cells (Fig. 4).
Therefore, one of ordinary skill in the art would be motivated to further modify the detection and treatment method comprising administering the 6FBJ MMP-7 antibody to a pancreatic cancer patient according to the combined teachings of Sagi, Dym, and Fukuda, to include the additional administration of oxaliplatin as taught by Almendro, in order to improve the efficacy of chemotherapy when administered in combination with an MMP-7 antibody.  Given what is known in the art, one would expect that inhibiting MMP-7 with the 6FBJ MMP-7 antibody when combined with oxaliplatin chemotherapy would produce similar outcomes as demonstrated in Almendro – namely, that tumor cells with inhibited MMP-7 would undergo increased cell death in response to treatment.
Claims 18-19, 21, and 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over Sagi 2013 (US 2013/0209491 A1), herein “Sagi”, Dym 2019 (https://doi.org/10.2210/pdb6FBJ/pdb; published January 30, 2019 ), herein “Dym”, Fukuda 2011, (DOI: 10.1016/j.ccr.2011.03.002) herein “Fukuda”, and Almendro 2009 (DOI: 10.1371/journal.pone.0004728), herein “Almendro”, as applied to claims 5-7, 11-13, 15-17, 20, 23, and 26 above, and further in view of Siena 2013 (DOI: 10.1111/imm.12190.), herein “Siena”, and Sakamoto 2006 (DOI: 10.1007/s00535-005-1724-7), herein “Sakamoto”.
The teachings of Sagi, Dym, Fukuda, and Almendro are described above.
Together Sagi, Dym, Fukuda, and Almendro do not teach the use of a nucleoside analogue (Claims 18 and 24), such as gemcitabine (Claims 19 and 25), in combination with MMP-7 inhibition nor do they teach that the dose of a chemotherapeutic agent is “less than the gold standard dose when used as a single agent”, as recited in Claim 21.  However, these deficiencies are cured by Siena and Sakamoto.
Siena teaches that gemcitabine induces cell death in cancer cells via the Fas/FasL pathway.
Sakamoto teaches that gemcitabine is “relatively effective against pancreatic cancer” (Introduction) and that treatment with low-dose gemcitabine (250mg/m2) resulted in lower toxicity and improved quality of life in pancreatic cancer patients when compared to patients treated with the standard dose (1000mg/m2) (Abstract; Table 3).
Because the state of the art teaches that MMP-7 inhibition can increase cells’ sensitivity to chemotherapeutic agents in part through the interaction of MMP-7 with the Fas/FasL pathway (Almendro), one of ordinary skill in the art would reasonably expect that inhibiting MMP-7 would also result in increased sensitivity to gemcitabine, which induces apoptosis through the Fas/FasL pathway, as taught by Sienna.  One would also anticipate that the gemcitabine treatment of pancreatic cancer would remain effective at doses lower than the gold standard, according to the low-dose regiment taught by Sakamoto – particularly when augmented by an MMP-7 antibody. Therefore, one of ordinary skill in the art would be motivated to further modify the method of detecting and treating pancreatic cancer through the co-administration of the 6FBJ MMP-7 antibody and oxaliplatin according to the combined teachings of Sagi, Dym, Fukuda, and Almendro by substituting the chemotherapy agent with gemcitabine and administering said agent at a lower than standard dose.  One would be motivated to do so in order to improve the efficacy of gemcitabine treatment in patients with pancreatic cancer, while also decreasing toxicity and improving the quality of life of said patients.
Claims 24-25 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Sagi 2013 (US 2013/0209491 A1), herein “Sagi”, Dym 2019 (https://doi.org/10.2210/pdb6FBJ/pdb; published January 30, 2019 ), herein “Dym”, Fukuda 2011, (DOI: 10.1016/j.ccr.2011.03.002) herein “Fukuda”, and Almendro 2009 (DOI: 10.1371/journal.pone.0004728), herein “Almendro”, as applied to claims 5-7, 11-13, 15-17, 20, 23, and 26 above, and further in view of Mondal 2017 (DOI: 10.1021/acs.molpharmaceut.7b00355), herein “Mondal”.
The teachings of Sagi, Dym, Fukuda, and Almendro are described above.  In summary, Sagi teaches a method of treating cancer with an MMP-7 antibody, Dym teaches an MMP-7 antibody comprising SEQ ID NOs: 3-8 of the instant disclosure, Fukuda teaches MMP-7 inhibition as a treatment for pancreatic cancer, and Almendro teaches that inhibiting MMP-7 increases the efficacy of chemotherapeutic agents.
Together they do not teach that the antibody and the chemotherapeutic agent are formulated in a single composition, nor do they teach that the chemotherapeutic agent is a nucleoside analogue or gemcitabine.  However, this deficiency is cured by Mondal.
Mondal teaches that co-formulation of the chemotherapeutic agent gemcitabine (GEM) with a tumor-targeting monoclonal antibody results in “significant enhancement in cellular uptake by tumor cells and reversal of GEM resistance, leading to enhanced tumor accumulation and consequent tumor regression” (Conclusion) in a pancreatic cancer model.
One of ordinary skill in the art would therefore be motivated by the combined teachings of Sagi, Dym, Fukuda, and Almendro to modify the method of detecting and treating cancer taught by Sagi to incorporate the 6FBJ MMP-7 antibody taught by Dym co-formulated with gemcitabine, as taught by Mondal, in an effort to increase the targeting specificity of gemcitabine to cells with elevated MMP-7 and further improve the treatment’s efficacy against chemo-resistant populations of cells in pancreatic cancer.  Given what is known in the art – specifically that MMP-7 is elevated in pancreatic cancer, as taught by Fukuda, that inhibiting MMP-7 increases apoptosis in response to a chemotherapeutic agent, as taught by Almendro, and that targeting gemcitabine to pancreatic cancer cells with an antibody improves its efficacy against gemcitabine-resistant cell populations, as taught by Mondal – one would reasonably expect the co-formulation of the 6FBJ MMP-7 taught by Dym antibody with gemcitabine to provide benefit over treatment with either agent alone.
Claim 15 is further rejected under 35 U.S.C. 103 as being unpatentable over Sagi 2013 (US 2013/0209491 A1), herein “Sagi”, and further in view of Fukuda 2011, (DOI: 10.1016/j.ccr.2011.03.002) herein “Fukuda”.
The teachings of Sagi are described above.  In summary, Sagi teaches a method of treating cancer with an inhibitory MMP-7 antibody wherein the Ki of the antibody towards MMP-7 is at least 5 times lower than a Ki of the antibody towards MMP-2 or MMP-9.
Sagi does not teach that the cancer is pancreatic cancer. However, this deficiency is cured by Fukuda.
Fukuda teaches that knockout of MMP-7 in a pancreatic ductal adenocarcinoma (PDA) mouse model limits tumor size and metastasis (Fig. 6; Abstract). Fukuda further demonstrates that “serum MMP7 level in human patients with PDA correlated with metastatic disease and survival”, wherein lower serum levels correlated with higher survival (Abstract; Fig. 7).
One of ordinary skill in the art would be motivated to modify the method of treating a disease taught by Sagi, to include pancreatic cancer as the target disease, according to the teachings of Fukuda.  Sagi teaches a method of treating cancer with an MMP-7 antibody, and Fukuda teaches that MMP-7 knockout reduces tumor burden and high MMP-7 levels correlate with a poor prognosis.  Accordingly, one would reasonably expect that inhibiting MMP-7 with an antibody would result in decreased tumor size, fewer metastases, and higher survival in a pancreatic cancer patient.
Claims 17 and 20 are further rejected under 35 U.S.C. 103 as being unpatentable over Sagi 2013 (US 2013/0209491 A1), herein “Sagi”, and Fukuda 2011, (DOI: 10.1016/j.ccr.2011.03.002) herein “Fukuda”, as applied to Claim 15 above, and in further view of Almendro 2009 (DOI: 10.1371/journal.pone.0004728), herein “Almendro”.
The teachings of Sagi and Fukuda are described above.
Together Sagi and Fukuda do not teach combining MMP-7 inhibition with a chemotherapeutic agent.  However, this deficiency is cured by Almendro.
Almendro teaches that MMP-7 contributes to chemoresistance of cancer cells through its interaction with the Fas/FasL pathway (Abstract; Fig. 8) and that inhibition of MMP-7 augments the ability of chemotherapeutic agent oxaliplatin to induce cell death in cancer cells (Fig. 4).
Therefore, one of ordinary skill in the art would be motivated to further modify the treatment method comprising administering an MMP-7 antibody to a pancreatic cancer patient according to the combined teachings of Sagi and Fukuda, to include the additional administration of oxaliplatin as taught by Almendro, in order to improve the efficacy of chemotherapy when administered in combination with an MMP-7 antibody. Given what is known in the art, one would expect that inhibiting MMP-7 with an antibody when combined with oxaliplatin chemotherapy would produce similar outcomes as demonstrated in Almendro – namely, that tumor cells with inhibited MMP-7 would undergo increased cell death in response to treatment.
Claims 18-19 and 21 are further rejected under 35 U.S.C. 103 as being unpatentable over Sagi 2013 (US 2013/0209491 A1), herein “Sagi”, Fukuda 2011, (DOI: 10.1016/j.ccr.2011.03.002) herein “Fukuda”, and Almendro 2009 (DOI: 10.1371/journal.pone.0004728), herein “Almendro”, as applied to Claims 17 and 20 above, and further in view of Siena 2013 (DOI: 10.1111/imm.12190.), herein “Siena”, and Sakamoto 2006 (DOI: 10.1007/s00535-005-1724-7), herein “Sakamoto”.
The teachings of Sagi, Fukuda, and Almendro are described above.
Together Sagi, Fukuda, and Almendro do not teach the use of a nucleoside analogue, such as gemcitabine, in combination with MMP-7 inhibition nor do they teach that the dose of a chemotherapeutic agent is “less than the gold standard dose when used as a single agent”.  However, these deficiencies are cured by Siena and Sakamoto.
Siena teaches that gemcitabine induces cell death in cancer cells via the Fas/FasL pathway.
Sakamoto teaches that gemcitabine is “relatively effective against pancreatic cancer (Introduction) and that treatment with low-dose gemcitabine (250mg/m2) resulted in lower toxicity and improved quality of life in pancreatic cancer patients when compared to patients treated with the standard dose (1000mg/m2) (Abstract; Table 3).
Because the state of the art teaches that MMP-7 inhibition can increase cells’ sensitivity to chemotherapeutic agents in part through the interaction of MMP-7 with the Fas/FasL pathway (Almendro), one of ordinary skill in the art would reasonably expect that inhibiting MMP-7 would also result in increased sensitivity to gemcitabine, which induces apoptosis through the Fas/FasL pathway, as taught by Sienna.  One would also anticipate that the gemcitabine treatment of pancreatic cancer would remain effective at doses lower than the gold standard, according to the low-dose regiment taught by Sakamoto – particularly when augmented by an MMP-7 antibody. Therefore, one of ordinary skill in the art would be motivated to further modify the method of treating pancreatic cancer through the co-administration of the an MMP-7 antibody and oxaliplatin according to the combined teachings of Sagi, Fukuda, and Almendro by substituting the chemotherapy agent with gemcitabine and administering said agent at a lower than standard dose.  One would be motivated to do so in order to improve the efficacy of gemcitabine treatment in patients with pancreatic cancer, while also decreasing toxicity and improving the quality of life of said patients.
Conclusion
No claim is allowed.


NEXT OFFICE 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 .
EXAMINER’S AMENDMENT
An examiner’s amendment to the record appears below. Should the changes and/or additions be unacceptable to applicant, an amendment may be filed as provided by 37 CFR 1.312. To ensure consideration of such an amendment, it MUST be submitted no later than the payment of the issue fee.
Authorization for this examiner’s amendment was given in an interview with Martin Moynihan on 02/03/2025.
The application has been amended as follows:
In The Specification:
In lines 28-29 on Pg. 6 of the Specification move the header “C,” from the end of line 29 to line 28 immediately preceding the word “Increase”, as follows:
C, Increase in percentage of cells undergoing apoptosis was plotted using mean values ± s.e.m. (grey bar plot). LOXL-2 Fab generated using same pipeline was used as a treatment control.
Reasons for Allowance
The following is an examiner’s statement of reasons for allowance:
Applicant’s amendments to the claims submitted 01/17/2025 have obviated rejections made under 35 USC § 112.  Likewise, applicant’s declaration under 37 CFR 1.130 filed 01/17/2025 has obviated rejections made under 35 USC § 103, which relied on the sequences taught by Dym, 2019 (PDB deposit 6FBJ; “monoclonal antibody targeting Matrix mellaoproteinase 7”).  Accordingly, all previously made rejections are withdrawn.
The nearest prior art of record is considered to be Sagi, 2013 (US 2013/0209491 A1), which teaches a method of generating anti-MMP-7 antibodies by co-immunization with a synthetic zinc mimicry compound and MMP-7 (Sagi claim 2).  Sagi further teaches that the resulting MMP-7 antibodies share many of the same instantly claimed properties (e.g., ¶0011) and may further be used in the treatment of cancers (¶0141).  However, Sagi does not disclose or suggest any sequences or antibody clone identifiers associated with the instantly claimed MMP-7 antibody.
All instant claims are limited by SEQ ID NOs: 3-8, which comprise the CDR sequences of monoclonal anti-MMP-7 antibody “6FBJ”.  Although Dym, 2019 (PDB deposit 6FBJ) discloses the full-length sequence of 6FBJ and was published prior to applicant’s effective filing date, applicant has provided a showing that the disclosure is applicant’s own work and does not qualify as prior art under the grace period provided for by 102(b)(1)(A).  Therefore, all claims are free of the prior art of record.
For these reasons, Claims 5-7, 11-13, 15, 18-21, 23-27, and 36 are allowed.
Conclusion
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee.  Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”

CITED REFERENCE SUMMARIES: Ref US20130209491A1: Claims:
A method of generating an antibody which inhibits a metalloenzyme, the method comprising immunizing a subject with: (i) a synthetic zinc mimicry compound having structural and electronic properties similar to a catalytic domain of the metalloenzyme; and (ii) the metalloenzyme, thereby generating the antibody which inhibits the metalloenzyme.
(i) a synthetic zinc mimicry compound having structural and electronic properties similar to a catalytic domain of the metalloenzyme; and
(ii) the metalloenzyme,
thereby generating the antibody which inhibits the metalloenzyme.
The method of claim 1 , wherein said metalloenzyme is MMP-7 or ALF.
The method of claim 1 , wherein said zinc mimicry compound has the formula (I):
wherein: wherein R=O—CH 2 —C(═O)NH—CH 2 —CH 2 —NH 2
wherein R=O—CH 2 —C(═O)NH—CH 2 —CH 2 —NH 2
The method of claim 1 , wherein said immunizing is effected by initially immunizing with (i) and subsequently immunizing with (ii).
The method of claim 1 , wherein said immunizing is effected by co-immunizing with (i) and (ii).
The method of claim 1 , wherein said metalloenzyme is not naturally expressed by the subject.
An antibody comprising an antigen recognition region which binds a catalytic site of anthrax lethal factor (ALF), wherein the antibody inhibits the activity of said ALF and wherein said antigen recognition region binds a compound having the formula (I):
The antibody of claim 7 , wherein said antigen recognition region binds the metal ion coordinating amino acids within said catalytic zinc site of said ALF and to said metal ion of said metal ion coordinating amino acids within said catalytic zinc site of said ALF.
An antibody comprising an antigen recognition region which binds a catalytic site of MMP-7, wherein the antibody inhibits the activity of said MMP-7 and wherein the Ki of the antibody towards said MMP-7 is at least 5 times lower than a Ki of the antibody towards MMP2 or MMP9.
- 15 . (canceled)
The antibody of claim 7 attached to a detectable moiety or a therapeutic moiety.
A method of treating a disease associated with imbalanced or abnormal activity of MMP-7 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the antibody of claim 11 , thereby treating the disease associate with imbalanced or abnormal activity of MMP-7 in the subject.
The method of claim 17 , wherein the disease is cancer or an inflammatory bowel disease.
A method of diagnosing a disease associated with imbalanced or abnormal activity of MMP-7 in a subject, the method comprising contacting a sample of the subject with the antibody of claim 11 so as to analyze expression of MMP-7, wherein an upregulation of expression of said MMP-7 is indicative of the disease associated with imbalanced or abnormal activity of MMP-7.
A method of treating or preventing anthrax disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the antibody of any of claim 7 , thereby treating or preventing the anthrax disease.
The method of claim 20 , wherein said administering is effected prophylactically.
A method of diagnosing anthrax infection in a subject, the method comprising contacting a sample of the subject with the antibody of claim 7 so as to analyze expression of ALF, wherein an expression of said ALF is indicative of anthrax infection.
A pharmaceutical composition comprising the antibody of claim 7 .
A pharmaceutical composition comprising the antibody of claim 11 .
Ref WO2008102359A1: Claims:
A compound having the general Formula (I):
wherein: m and n are each independently an integer from 1 to 6;
X 1 -X 3 and Yi-Y 3 are each independently O or S;
Ri-R 3 are each indepdnently selected from the group consisting of hydrogen, alkyl, and cycloalkyl; and
R is (CH 2 )x-C(=O)NR I -(CH 2 )y-NR'R" whereas: x and y are each independently an integer from 1 to 6; and
R' and R" are each independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.
The compound of claim 1, having the Formula (II)
A compound having the Formula (I I)-
R = -CH 2 -C(=O)NH-CH 2 -CH 2 -NH 2
An antibody comprising an antigen recognition region capable of specifically binding the compound of claim 1, 2 or 3.
An antibody comprising an antigen recognition region which comprises CDR amino acid sequences set forth in SEQ ID NO. 7, 8, 9, 10, 11 and 12
The antibody of claim 5, wherein said CDR amino acid sequence is encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NO: 13, 14, 15, 16, 17 and 18.
The antibody of claim 4, is capable of inhibiting an activity of a metalloproein.
The antibody of claim 7, wherein said is a matrix metalloprotease.
The antibody of claim 7, wherein said a gelatinase.
The antibody of claim 9, wherein said gelatinase is selected from the group of MMP-2 and MMP-9.
A method of producing a metalloprotein inhibitor, the method comprising generating antibodies directed at the compound of claim 1, 2 or 3, thereby producing the metalloprotein inhibitor.
The method of claim 11, wherein said antibodies are polyclonal antibodies.
The method of claim 11, wherein said antibodies are monoclonal antibodies.
A pharmaceutical composition comprising the antibody of claim 4 and a pharmaceutically acceptable carrier.
A method of treating a disease associated with imbalanced or abnormal activity of metalloproteins in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of any one of the antibodies of claim 4-10, thereby treating a disease associate with imbalanced or abnormal activity of metalloproteins in the subject.
The method of claim 15, wherein the disease is an inflammatory bowel disease.
A method of inhibiting matrix metalloprotease activity in a cell, the method comprising contacting the cell with any one of the antibodies of claim 4-10, thereby inhibiting the matrix metalloprotease activity in the cell.
Ref WO2008102359: Claims:
WHAT IS CLAIMED IS: 1. A compound having the general Formula (I): wherein: m and n are each independently an integer from 1 to 6; X1-X3 and Yi-Y3 are each independently O or S; Ri-R3 are each indepdnently selected from the group consisting of hydrogen, alkyl, and cycloalkyl; and R is (CH2)x-C(=O)NRI-(CH2)y-NR'R" whereas: x and y are each independently an integer from 1 to 6; and R' and R" are each independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. 2. The compound of claim 1, having the Formula (II) wherein R = 3. A compound having the Formula (I I)- R = -CH2-C(=O)NH-CH2-CH2-NH2 4. An antibody comprising an antigen recognition region capable of specifically binding the compound of claim 1, 2 or 3. 5. An antibody comprising an antigen recognition region which comprises CDR amino acid sequences set forth in SEQ ID NO. 7, 8, 9, 10, 11 and 12 6. The antibody of claim 5, wherein said CDR amino acid sequence is encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NO: 13, 14, 15, 16, 17 and 18. 7. The antibody of claim 4, is capable of inhibiting an activity of a metalloproein. 8. The antibody of claim 7, wherein said is a matrix metalloprotease. 9. The antibody of claim 7, wherein said a gelatinase. 10. The antibody of claim 9, wherein said gelatinase is selected from the group of MMP-2 and MMP-9. 11. A method of producing a metalloprotein inhibitor, the method comprising generating antibodies directed at the compound of claim 1, 2 or 3, thereby producing the metalloprotein inhibitor. 12. The method of claim 11, wherein said antibodies are polyclonal antibodies. 13. The method of claim 11, wherein said antibodies are monoclonal antibodies. 14. A pharmaceutical composition comprising the antibody of claim 4 and a pharmaceutically acceptable carrier. 15. A method of treating a disease associated with imbalanced or abnormal activity of metalloproteins in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of any one of the antibodies of claim 4-10, thereby treating a disease associate with imbalanced or abnormal activity of metalloproteins in the subject. 16. The method of claim 15, wherein the disease is an inflammatory bowel disease. 17. A method of inhibiting matrix metalloprotease activity in a cell, the method comprising contacting the cell with any one of the antibodies of claim 4-10, thereby inhibiting the matrix metalloprotease activity in the cell.
A compound having the general Formula (I): wherein: m and n are each independently an integer from 1 to 6; X1-X3 and Yi-Y3 are each independently O or S; Ri-R3 are each indepdnently selected from the group consisting of hydrogen, alkyl, and cycloalkyl; and R is (CH2)x-C(=O)NRI-(CH2)y-NR'R" whereas: x and y are each independently an integer from 1 to 6; and R' and R" are each independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.
The compound of claim 1, having the Formula (II) wherein R =
A compound having the Formula (I I)- R = -CH2-C(=O)NH-CH2-CH2-NH2
An antibody comprising an antigen recognition region capable of specifically binding the compound of claim 1, 2 or 3.
An antibody comprising an antigen recognition region which comprises CDR amino acid sequences set forth in SEQ ID NO. 7, 8, 9, 10, 11 and 12
The antibody of claim 5, wherein said CDR amino acid sequence is encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NO: 13, 14, 15, 16, 17 and 18.
The antibody of claim 4, is capable of inhibiting an activity of a metalloproein.
The antibody of claim 7, wherein said is a matrix metalloprotease.
The antibody of claim 7, wherein said a gelatinase.
The antibody of claim 9, wherein said gelatinase is selected from the group of MMP-2 and MMP-9.
A method of producing a metalloprotein inhibitor, the method comprising generating antibodies directed at the compound of claim 1, 2 or 3, thereby producing the metalloprotein inhibitor.
The method of claim 11, wherein said antibodies are polyclonal antibodies.
The method of claim 11, wherein said antibodies are monoclonal antibodies.
A pharmaceutical composition comprising the antibody of claim 4 and a pharmaceutically acceptable carrier.
A method of treating a disease associated with imbalanced or abnormal activity of metalloproteins in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of any one of the antibodies of claim 4-10, thereby treating a disease associate with imbalanced or abnormal activity of metalloproteins in the subject.
The method of claim 15, wherein the disease is an inflammatory bowel disease.
A method of inhibiting matrix metalloprotease activity in a cell, the method comprising contacting the cell with any one of the antibodies of claim 4-10, thereby inhibiting the matrix metalloprotease activity in the cell.