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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Effective filing date is 18 March 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 16 March 2023, is being considered by the examiner.
Status of Application, Amendments, and/or Claims
Claims 1-16 are pending and the subject of this action.
Claim Objections
Claim 7 is objected to for a minor informality. The claim contains a grammatical error, found in the following passage: “a VH of sequence of SEQ ID NO:22.” It is suggested that this be amended to read as follows: “a VH sequence of SEQ ID NO: 22.” Appropriate corrections are required.
Claim 12 is objected to for a minor informality. The claim contains a grammatical error, found in the following passage: “a VH of sequence of SEQ ID NO:22.” It is suggested that this be amended to read as follows: “a VH sequence of SEQ ID NO: 22.”
Claim Rejections - 35 USC § 112
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.
Written Description
Claims 1 and 2 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1 and 2 are describing a method for treating liver inflammation using an anti-netrin-1 antibody. The written description and prior art show that the antibodies disclosed in the written description effectively inhibit the interaction between netrin-1 and UNC5. However, neither the specification or the prior art teaches a genus of antibodies that inhibit this interaction. What is disclosed within the instant application is simply one species (i.e. a set of CDRs that can bind an epitope on a polypeptide contained within SEQ ID NO: 33), and cannot be considered representative of the genus. The bounds of the claim extend to any antibody capable of binding/inhibiting netrin-1 in fashion that treats liver inflammation. However, neither the specification or the prior art teaches a genus of antibodies that can treat liver inflammation or bind to an epitope within the amino acid sequence contained within SEQ ID NO:33.
This gulf between species and genus is exemplified by a study performed by Edwards et al (Edwards et al. 2003. The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BlyS. Journal of Molecular Biology 334:103-118) in which over a thousand antibodies, capable of binding the same 51 kDa protein, were isolated, and from which 1098 distinct VH and 705 VL sequences were identified. Thus, the disclosure of one set of CDRs is insufficient to prove that the applicant was in possession of sufficient number of representative antibodies to claim the entire genus.
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.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 9 is rejected as vague and indefinite for reciting GenBank ascension numbers. It is well known in the art that ascension numbers can be altered, deleted, amended, or revised over time by various inventors. Hence, one of ordinary skill in the art would be unable to discern the bounds of the claimed invention. Amending the claims to specify and uniquely identify the claimed human constant heavy chain and human constant light chain by sequence identifier (i.e. SEQ ID NO) can obviate the rejections.
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.
Claims 1-16 are rejected under 35 U.S.C. 103 as being unpatentable over US20060019896 A1 (herein Li) and US20210113687 A1 (herein Moore) in view of Lahlali et al. Netrin-1 protects hepatocytes against cell death through sustained translation during the unfolded protein response. Cell Mol Gastroenterol Hepatol. Jan 9;2(3):281-301 (herein Lahlali) and WO2015104360 A1 (herein Delcros), with Chakraborty et al. (2012) Mechanisms and biomarkers of apoptosis in liver disease and fibrosis. Int J Hepatol. 2012:648915. doi: 10.1155/2012/648915. Epub 2012 Apr 9 (herein Chakraborty) providing additional evidentiary value.
In regard to claims 1 and 10, Li teaches a method of decreasing/treating inflammation through the use of monoclonal anti-netrin-1 antibodies ([0309][0310][0068][0162][0070][0449, and claims 29 and 30). Additionally, Moore also teaches a similar method of using monoclonal anti-netrin-1 antibodies to treat inflammation ([0068][0118][0107]).
Li and Moore do not teach the specific targeting of the liver when describing a method of treating inflammation using anti-netrin-1 antibodies, nor do they provide an example of an anti-netrin-1 antibody that inhibits the interactions between netrin-1 and dependence receptors.
Lahlali teaches that netrin-1 is up-regulated in inflammation (background and aims). Lahlali also teaches that Netrin-1 plays a role in cell survival during the unfolded protein response (UPR), which is a hallmark of chronic liver conditions (background and aims). Lahlali further teaches that netrin-1 translation persists throughout UPR-induced translational inhibition, through the utilization of an IRES (summary).
As taught by Li and Moore, blocking the interaction between netrin-1 and its receptors can be used as a method for treating inflammation (Li, [0062])(Moore, [0068][0118][0107]). Li and Moore teach that netrin-1 overexpression limits apoptosis and reduces macrophage migration ([Moore, [0218][0221]). Both of these effects lead to a pro-inflammatory environment, as a result of the prolonged activity of innate immune cells within the affected tissue. More specifically, netrin-1 prevents apoptosis and emigration of macrophages from the site of injury, causing extended pro-inflammatory signaling.
Delcros teaches an anti-netrin-1 antibody capable of inhibiting the interaction between netrin-1 and dependence receptors, such as UNC5B. In this disclosure a dose-dependent inhibition of netrin-UNC5B binding was shown upon the addition of the anti-netrin-1 antibody in an ELISA-like assay (figure 2). Additionally, it was shown that inhibition of netrin-1 resulted in increased caspase-3 activity, apoptosis levels, in human lung adenocarcinoma epithelial lung cells (figure 5).
These disclosures align with previous descriptions of prolonged liver injury/inflammation. Briefly, during an elongated injury phase, innate immune cells migrate towards the injured tissue, release proinflammatory cytokines, downregulate proapoptotic molecules, upregulate antiapoptotic molecules (such as netrin-1), and allow for a microenvironment that leads to the accumulation of damaged hepatocytes, which eventually develop a mechanism for apoptosis evasion (page 3 hepatocellular carcinoma section, Chakraborty). When applying the teaching of Lahlali to those of Li, Moore, and Chakraborty et al, it is evident that at least one mechanism leading to prolonged inflammation and apoptosis evasion in liver disease involves the abundance of netrin-1.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the method of administering anti-netrin-1 antibodies to a patient suffering from liver inflammation. As taught by Lahlali, netrin-1 plays a critical role in the cell survivability in UPR, which is a hallmark of liver disease, and is in abundance throughout inflamed liver tissue. Chakraborty, provides a mechanism in which chronic inflammation persists and progresses through the abundance of netrin-1, an anti-apoptosis molecule. Li and Moore provide clear motivation for the use of anti-netrin-1 antibodies for reducing inflammation (i.e. the inhibition of the antiapoptotic and anti-emigratory properties of netrin-1). Delcros provides a suitable antibody to inhibit netrin-1-dependence receptor binding. Due to the prior art presented, there would have been a reasonable expectation of success associated with a method of treating liver inflammation with anti-netrin-1 antibodies.
In regard to claim 2, Li, Moore, Lahlali, and Chakraborty teach a method for treating liver inflammation, as described for claims 1 and 10.
Delcros teaches the use of a monoclonal antibody or binding fragment thereof that specifically binds to a peptide of SEQ ID NO:33 (page 3 line 34).
In regard to claims 3 and 11, Li, Moore, Lahlali, and Chakraborty teach a method for treating liver inflammation, as described for claims 1 and 10.
Delcros teaches a monoclonal anti-netrin-1 antibody or binding fragment thereof a variable domain VH comprising (page 4-5 lines 35(p4)-2(p5) and page 5 lines 7-11):
a H-CDR1 having a sequence set forth as SEQ ID NO: 28
a H-CDR2 having a sequence set forth as SEQ ID NO: 29
a H-CDR3 having a sequence set forth as SEQ ID NO: 29
a variable domain VL comprising:
L-CDR1 having a sequence set forth as SEQ ID NO: 31
L-CDR2 having a sequence set forth as SEQ ID NO: 32
L-CDR3 having a sequence set forth as SEQ ID NO: 9
In regard to claims 4-6, Li, Moore, Lahlali, and Chakraborty teach a method for treating liver inflammation, as described for claims 1 and 10.
Delcros teaches monoclonal antibodies, that may be humanized with IgG1 constant heavy chain or IgG1 constant light chain (kappa), or binding fragments thereof that comprise VH-VL pairs of the following sequences (page 5 table, page 5 lines 20-24):
SEQ ID NO: 27 and 19
SEQ ID NO: 20 and 14
SEQ ID NO: 21 and 15
SEQ ID NO: 22 and 16
SEQ ID NO: 23 and 17
SEQ ID NO: 24 and 17
SEQ ID NO: 25 and 16
SEQ ID NO: 23 and 17
SEQ ID NO: 24 and 17
SEQ ID NO: 25 and 16
SEQ ID NO: 26 and 17
SEQ ID NO: 22 and 17
SEQ ID NO: 25 and 18
SEQ ID NO: 21 and 16
In regard to claims 7-9, Li, Moore, Lahlali, and Chakraborty teach a method for treating liver inflammation, as described for claims 1 and 10.
Delcros teaches monoclonal antibodies, that may be humanized with IgG1 constant heavy chain or IgG1 constant light chain (kappa), or binding fragments thereof that comprise a VH and VL sequences of SEQ ID NO: 22 and 16, respectively (page 5 table, page 5 lines 20-24).
In regard to claim 12, Li, Moore, Lahlali, and Chakraborty teach a method for treating liver inflammation, as described for claims 1 and 10.
Delcros teaches monoclonal antibodies or binding fragments thereof that comprise a VH and VL sequences of SEQ ID NO: 22 and 16, respectively (page 5 table, page 5 lines 20-24).
In regard to claims 13-16, Li, Moore, Lahlali, and Chakraborty teach a method for treating liver inflammation using a monoclonal anti-netrin-1 antibody, as described for claims 1 and 10.
It would be obvious to those skilled in the art that the antibodies taught in the prior art would possess the same inherent characteristics as those presented in the instant application, as Delcros teaches the exact CDRs utilized in the instant application. Furthermore, species-dependent arguments would be invalid in this case, as the genus of anti-netrin-1 antibody, capable of blocking the interactions between netrin-1 and the dependence receptors, would possess an identical biological effect as those described in the instant application. Although the prior art is silent regarding the effect the antibodies have towards the markers described in claims 13-16, two therapeutic treatments using antibodies with identical function (i.e. blocking netrin-1-dependence receptor interactions) would have the same effect on the inflammatory marker listed in claims 13-16, as the changes in the assessed marker result from inhibition of the netrin-1-dependence receptor interaction. As established in Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003), there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference.
Conclusion
All claims rejected.
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/MATTHEW CURRAN METCALF/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647