Office Action 2: Notice of Allowance (2025-02-26)

CLAIMS:
In the Claims:

1-4. (Cancelled)23

5\. (Currently Amended) 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 an antibody, having complementarity determining region amino acid sequences as set forth in: SEQ ID NOs: 3, 4 and 5, sequentially arranged from N to C on a light chain of the antibody; and SEQ ID NOs: 6 , 7 and 8, sequentially arranged from N to C on a heavy chain of the antibody, thereby treating the disease associate with imbalanced or abnormal activity of MMP-7 in the subject.

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

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

8-10. (Cancelled)99

11\. (Currently Amended) 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 an antibody which having complementarity determining region amino acid sequences as set forth in: SEQ ID NOs: 3,4and 5, sequentially arranged from N to C on a light chain of the antibody; and SEQ ID NOs: 6, 7 and 8, sequentially arranged from N to C on a heavy chain of the antibody

upon confirmation that said amount of said MMP-7 is above a predetermined level, thereby treating the cancer.

12\. (Currently Amended) 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 an antibody , having complementarity determining region amino acid sequences as set forth in: SEQ ID NOs: 3, 4 and 5, sequentially arranged from N to C on a light chain of the antibody; and SEQ ID NOs: 6, 7 and 8, sequentially arranged from N to C on a heavy chain of the antibody; 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\. (Original) The method of claim 11, wherein said analyzing is effected using an antibody.

14\. (Cancelled)

15\. (Currently Amended) A method of treating pancreatic cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an antibody which down-regulates MMP-7 activity and a chemotherapeutic agent, 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, wherein the antibody has complementarity determining region amino acid sequences as set forth in: SEQ ID NOs: 3, 4 and 5, sequentially arranged from N to C on a light chain of the antibody;
and SEQ ID NOs: 6, 7 and 8, sequentially arranged from N to C on a heavy chain of the antibody.

16-17 (Cancelled)

18\. (Currently Amended) The method of claim -715, wherein said chemotherapeutic agent is a nucleoside analogue.

19\. (Currently Amended) The method of claim 18, wherein said nucleoside analogue comprises gemcitabine.

20\. (Currently Amended) The method of claim--?15, wherein said chemotherapeutic agent is Oxaliplatin.

21\. (Currently Amended) The method of claim--? 15, wherein the dose of said chemotherapeutic agent is less than the gold standard dose when used as a single agent.

22\. (Cancelled)

23\. (Currently Amended) An article of manufacture comprising an antibody , having complementarity determining region (CDR) amino acid sequences as set forth in: SEQ ID NOs: 3, 4 'and 5, sequentially arranged from N to C on a light chain of the antibody; and SEQ ID NOs: 6, 7 and 8, sequentially arranged from N to C on a heavy chain of the antibody and a chemotherapeutic agent.

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

25\. (Curently Amended) The article of manufacture of claim 24, wherein said nucleosideanalogue comprises gemcitabine.

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

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

28-35. (Cancelled)2934

36\. (New) The method of claim 7, wherein the pancreatic cancer is pancreatic adenocarcinoma.

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.”

APPLICANT REBUTTAL: REMARKS
Reconsideration of the above-identified application in view of the remarks following is respectfully requested.
Claims 5-7, 11-13, 15-21 and 23-27 are pending in this Application. Claims 5- 7, 11-13, 16 and 23-27 have been rejected under 35 U.S.C. 112, second paragraph. Claims 15 and 17-21 have been rejected under 35 U.S.C. 112, first paragraph. Claims 5-7, 11-13, 15-21 and 23-27 have been rejected under 35 U.S.C. 103.
Claims 5, 11, 12, 15, 18, 19, 23 and 25 have now been amended. Claims 16 and 17 have now been cancelled. New claim 36 has now been added.
Drawings
The Examiner has objected to the drawings stating that 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.
The Examiner's objection is respectfully traversed.
The first panel of Figure 4C does indeed relate to a Western Blot showing FasL expression in cell lysates with or without GSM-192 Fab treatment, as stated in the Figure legend. The y axis measures the percentage of AspC-l cells that are apoptotic as a result of treatment. In order to further clarify this figure, the figure legend has been amended to recite that the cells are AspC-1 cells - see page 3 of the instant response.
Amendments to the Abstract
The abstract of the disclosure was objected to for not being in a narrative form and not effectively summarizing the invention as claimed.
The abstract has now been amended to more fully correspond with the claimed invention.
Amendments to the Claims
35 U.S.C.
@
,
second
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h rejection
Claims 5-7, 11-13, 16 and 23-27 were rejected under 35 U.S.C. 112, second paragraph for being indefinite. Specifically, claims 5, 11-12, 16 and 23 recite terms in parentheses which renders the claims unclear.
Claims 5, 11-12 and 23 have been amended such that they no longer recite terms in parentheses. Claim 16 has been cancelled, rendering the rejection to this claim moot.
Claims 5-7, 11-13, 16 and 23-27 are rejected for requiring the limitation of the antibody "which binds to a catalytic site of MMP-7". The Examiner states that the disclosure does not show that the antibody binds to the catalytic site, but rather to exosites close to the conserved active site.
Whilst traversing Examiner's rejection, Applicant has now amended claims 5, 11-12 and 23 such that they no longer recite this contentious language. Applicant asserts that inclusion of the antibody CDR segunences sufficiently describes the claimed antibody.
35 U.
S.C.
#
112, first
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ara
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ection
Claims 15 and 17-21 were rejected under 35 112, first pagraph, as failing to comply with the written description requirement. The Examiner finds that the specification disloses a single antibody that conforms to the claim requirements which is not sufficient for complianc with the written description requirement.
The Examiner's rejection is traversed.
Notwithstanding, in the interest of expediting prosecution of this case, claim 15 has now been amended to recite the limitation of the non-rejected claim 16.
35 U.S.
C.
#
103 re
j
ection
Claims 5-7, 11-13 and 15-16 are rejected under 35 U.S.C. 103, as being unpatenable over Sagi 2013 (US2013/0209491), herein "Sagi" and further in view of Dym 2019
(https://d
oi.org/10
/pdb6FBJ/
p
db;
published January 30, 2019, herein "Dym" and Fakuda 2011
(https://p
nc.
ncbi.n
lm.
nih
.go
v/articles
/P
MC8
.
The Examiner states that "Sagi" discloses MMP-7 targeting antibodies for the treatment of cancer. The Examiner notes that "Sagi" does not teach pancreatic cancer, nor the MMP-7 antibody that comprises CDRs as set forth in SEQ ID NOs: 3-8. The Examiner finds that this would be obvious in view of "Dym" who discloses antibodies having the claimed CDRs and further in view of "Fakuda" who teaches that knockout of MMP-7 in pancreatic ductal andenocarcinoma (PDA) mouse model limits tumor size and metastatsis.
Claims 17, 20, 23 and 26 are rejected under 35 U.S.C. 103, as being unpatenable over Sagi 2013 (US2013/0209491), herein "Sagi" and further in view of Dym 2019
(https:
//doi.org
p
db6
FBJ/p
db;
published January 30, 2019, herein "Dym" and
Fakuda 2011
(htt
ps
://pmc.ncbi
.
nlm.nih
.g
ov/articles/PMC
and further in view of Almendro 2009, herein "Almendro".
The Examiner states that the teachings of "Sagi", "Dym" and "Fakuda" are described above. These references do not teach combination with a chemotherapeutic agent. The Examiner however, finds this obvious in view of "Almendro who teaches that MMP-7 contributes to chemoresistance of cancer cells and that inhibition of MMP- 7 aguments the ability of chemotherapeutic agents to induce cell death in cancer cells.
Claims 18-19, 21 and 24-25 are rejected under 35 U.S.C. 103, as being unpatenable over Sagi 2013 (US2013/0209491), herein "Sagi" and further in view of Dym 2019
(https://d
oi.org
pdb6
FBJ/pdb;
published January 30, 2019, herein "Dym" and Fakuda 2011
(https
:
//pmc.ncbi.n
l
m.nih.
go
v/articles/PMC
herein "Fakuda" and further in view of Almendro 2009, herein "Almendro" and further in view of Siena, 2013 and Sakanoto, 2006.
The Examiner states that the teachings of "Sagi", "Dym", "Fakuda" and "Almendro" are described above. These references do not teach that the dose of the chemotherapeutic agent is less than the gold standard dose which used as a single agent. The Examiner finds that this would be obvious in view of "Siena" and "Sakamoto".
The Examiner has further rejected claims 24-25 and 27 under 35 U.S.C. 103 as being unpatentable over Sagi 2013 (US2013/0209491), herein "Sagi" and further in view of Dym 2019
(https://d
oi.org/1
0/pdb6FBJ/
p
db;
published January 30, 2019, herein "Dym" and Fakuda 2011
(h
ttps://
pmc.n
cbi.
nlm
.
nih.
go
v/artic
l
es/PMC
herein "Fakuda" and further in view of Almendro 2009, herein "Almendro", as appliced to claims 5-7, 11, 13, 15-17, 20, 23 and 26 and further in view of Mondal 2017, herein "Mondal".
The Examiner states that the teachings of "Sagi", "Dym", "Fakuda" and "Almendro" are described above. These references do not teach that the antibody and the chemotherapeutic agent are formulated in a single composition, not that the chemotherapeutic agent is a nucleoside analogue. The Examiner finds that this would be obvious in light of "Mondal" who teachs co-formulation of a chemotherapeutic agent and a tumor-targeting monoclonal antibody.
The Examiner's rejections are respectfully traversed.
The Examiner provided a 4 page document to the USPTO as the "Dym" reference - see Appendix A. The four page document includes a reference to the
following paper: "Novel monoclonal antibody targeting Matrix metalloproteinase 7 shows therapeutic potential against pancreatic cancer".
The authors of the paper are as follows: Mohan V, Gaffney J, Klepfish M, Akbareian S, Grunwald B, Akkari L, Solomonov I, Dym O, Eisenstein M, Joyce J, Kruger A, Edwards D, Sagi I.
Applicant notes that the reference does not include the CDRs of the claimed antibody. As such, the reference cited in non-enabling, and the rejection is not relevant.
Notwithstanding the improper citation of references set forth by the Examiner, Applicants respectfully request the withdrawal of this rejection on the grounds that the "Dym" reference is not prior art relative to the instant application.
As evidenced by the attached Declaration of Irit Sagi under 37 CFR 1.132, Dym O, was identified as author of the above publication for her research efforts conducted under the direct supervision and direction of Irit Sagi and is therefore not an inventor.
In view of the fact that the reference "Dym" is not a prior art reference relative to the instant application, all rejections which include this prior art are no longer valid and should be withdrawn.
The Examiner has further rejected claim 15 as being unpatentable over "Sagi" in view of "Fukuda".
The Examiner states that "Sagi" discloses MMP-7 targeting antibodies for the treatment of cancer. The Examiner notes that "Sagi" does not teach pancreatic cancer. The Examiner finds that this deficiency is cured by "Fakuda" who teaches that knockout of MMP-7 in pancreatic ductal andenocarcinoma (PDA) mouse model limits tumor size and metastatsis.
The Examiner's rejection is traversed.
Notwithstanding, claim 15 has now been amended to recite the limitation of claim 17.
The Examiner has rejected claims 17 and 20 under 35 U.S.C. 103 as being unpatentable over "Sagi" in view of "Fukuda" and further in view of "Almendro".
The Examiner states that neither "Sagi" nor "Fakuda" teach combination with a chemotherapeutic agent; however this deficiency is cured by Almendro.
The Examiner's rejection is traversed.
Applicant asserts that a synergistic effect is sufficient to establish non- obviousness, even when each component of a composition is individually known to be
useful for the same purpose (which in this case the Applicant denies) - see for example MPEP 716.02(a).
Furthermore, the court in re Soni stated:
"Unexpected  results are useful in the obviousness
determination because they provide evidence that the invention is not obvious to one of ordinary skill in the art." In re Soni, 54 F.3d
746 (Fed. Cir. 1995)
The application further provides results testifying to the unexpected effect due to the combination of the claimed antibody with a chemotherapeutic agent. Pancreatic ductal adenocarcinoma cells are inherently capable of robust resistance to chemotherapeutic agents. The specification provides results showing the effectiveness of the claimed antibody in rescuing PDAC AspC-1 cells from gemcitabine (GEM) mediated drug resistance. Treatment of AspC-1 cells yielded an ICso of 126.6±40.5 nM GEM+ PBS group. Co-treatment of the claimed antibody and various concentrations of GSM-1 92 showed a marked reduction of ICso of GEM to 14.2± 1.52 nM (Figures 1 1 A- B).
Applicants submit that due to the synergistic activity of the claimed combinations of agent, the claims are not rendered obvious over Sagi" in combination with "Fukuda" and "Almendro".
The Examiner has rejected claims 18-19 and 21 under 35 U.S.C. 103 as being unpatentable over "Sagi" in view of "Fukuda" and further in view of "Almendro" and further in view of "Siena" and "Sakamoto".
The Examiner's rejection is traversed.
Applicanant relies on their argument as to the patentability of claims 17 and 20 with respect to "Sagi", "Fukuda" and "Almendro' to overcome the instant rejection.
Since neither "Siena" nor "Sakamoto" disclose a synergistic effect of the claimed antibody and chemotherapeutic agent, the cited combination of references do not render obvious claims 18-19 and 21.
In view of the above amendments and remarks it is respectfully submitted that claims 5-7, 11-13, 15, 18-21, 23-27 and 36 are now in condition for allowance. A prompt notice of allowance is respectfully and earnestly solicited.
Should the Examiner have any questions or comments as to the form, content, or entry of this paper, the Examiner is requested to contact the undersigned at the
telephone number below prior to mailing the next Official Action. Similarly, if there are any further issues yet to be resolved to advance the prosecution of this application to issue, the Examiner is requested to telephone the undersigned counsel.
Any fees associated with this paper, for its entry into the record, may be charged to Deposit Account No. 50-1407.
During the pendency of this application, the Commissioner for Patents is hereby authorized to charge payment of any filing fees for presentation of extra claims under 37 CFR § 1.16 and any patent application processing fees under 37 CFR § 1.17, or credit any overpayment, to Deposit Account No. 50-1407.
The Commissioner for Patents is hereby authorized to treat any concurrent or future reply, requiring a petition for extension of time under 37 CFR § 1.136 for its timely submission, as incorporating a petition for extension of time for the appropriate length of time if not submitted with the reply.
Recognizing that Internet communications are not secure, I hereby authorize the USPTO to communicate with me and any other practitioner of record under 37 CFR @ 1.33 and 37 CFR @ 1.34 concerning any subject matter of this application via electronic mail or instant messaging. I understand that a copy of these communications may be made of record in the application file (MPEP § 502.03).
Respectfully submitted,


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 .