Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-19 are pending and are currently under consideration.
Information Disclosure Statement
The listing of references at the end of 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.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 1 (and dependent claims 2-5, 9-13, and 16-18) is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: a correlation step that relates back to the preamble of the claim such that the detection of phosphorylated RelB protein is indicative of a poor prognosis. Including the phrase, “good prognosis” is an indistinct alternative that is not reflective of the subject matter which the applicant regards as their invention. For example, what level of phosphorylated RelB would be indicative of a good prognosis? As written, the metes and bounds of the claim cannot be determined. Dependent claims 2-5, 9-13, and 16-18 are included in this rejection because they do not cure this issue.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 18 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 18 states that the subject is a mammal. However, it’s dependent from Claim 11 which also states that the subject is a mammal. Thus, claim 18 is not further limiting of Claim 11. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for 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. This is a Written Description rejection.
The claims are broadly drawn to an in-vitro method of detecting phosphorylated RelB protein (SEQ ID NO:1) at serine residue 472 in cancer cells. The specification teaches [0012] that the detection of phosphorylated RelB at serine 472 is accomplished by “using an antibody”. However, disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, does not provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011) (patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties). See also MPEP 2163.II.A.3(a). All of the claims, except claim 9, provide no specific antibody structures. See paragraph 14 for more discussion regarding claim 9.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin.
It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. For example, MacCallum et al. (Journal of Molecular Biology, Vol. 262, pg. 732-745. 1996) analyzed many different antibodies for interactions with antigen and state that while no single residue is in contact with the antigen in all structures and CDR3 of the heavy and light chain dominate (pg. 733, paragraph bridging columns), contacts are more common at CDR residues which are located centrally within the combining site and non-contacting residues within the CDRs are important in defining "canonical" conformations (Abstract). Also, Pascalis et al. (The Journal of Immunology, pg. 3076-3084, 2002) demonstrate that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site (see page 3079, right col.). Although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left col.). The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al. (Biochemical and Biophysical Research Communications, Vol. 307, pg. 198-205., 2003) which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (Abstract). Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left col.).
Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function. Rudikoff et al., (Proceedings of the National Academies of Sciences, Vol. 79, pg. 1979-1983, 1982) teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (Abstract).
The references demonstrate that an antibody must comprise all 6 CDRs in order to maintain the antigen binding specificity and affinity which is characteristic of the immunoglobulin. The instant claims fail to meet the requirements for disclosure because the antibody is described solely by the antigen to which it binds – an antibody that binds to phosphorylated RelB protein at serine 472.
What applicants are in possession of is the mouse monoclonal antibody produced by clone RA3-AF3 [0110-0111]. Alternatively, regarding claim 9, applicants are in possession of an antibody comprising the VH chain of SEQ ID NO: 12 and the VL chain of SEQ ID NO:13. (See Table 4 on page 26) or an antibody comprising the HCDR1, HCDR2, and HCDR3 of SEQ ID Nos: 9, 10, and 11, respectively AND the LCDR1, LCDR2, and LCDR3 of SEQ ID Nos: 6, 7, and 8, respectively, but not the full scope of the claims inclusive of “functionally-conservative variants”. As discussed above (paragraph 12), even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function.
Moreover, the claimed antibody corresponds to a broad genus of antibodies capable of specifically binding to the indicated antigen (SEQ ID NO:1). They may be polyclonal antibodies, monoclonal antibodies, recombinant, humanized, synthetic, or chimeric antibodies, and fragments thereof, including F(ab) and F(ab')2. Most importantly, the claimed genus of antibodies can also have a broad range of structures at the antibody-antigen interface to bind to the peptide with the amino acid sequence of SEQ ID NO: 1.
In contrast to the broad genus of antibodies claimed, the applicant reduces to practice a single mouse monoclonal antibody with defined VH and VL regions. Therefore, claims 1-19 are rejected for failing to provide written description of the broad genus of antibody structures because the specification is only in possession of one species correlated with the claimed function (binding the peptide consisting of SEQ ID NO: 1) and fails to demonstrate possession of a representative number of species within the claimed genus.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-3, 5-7, 9-13, and 15-19 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US20180156819 (Baud et al. June 7, 2018).
As to claim 1, Baud et al. teach [0026, 0130] monitoring the phosphorylation status of RelB-serine 472 by appropriate reagents (in vitro- see para. 0030) appears to be a reproducible and easy way to monitor the activation level of the RelB-dependent NEκB pathway and that the present inventors also demonstrate for the first time that the RelB subunit of NEκB, once phosphorylated at serine 472, induces the migration of cells (and notably metastatic cancer cells) [0027]. The reference further teaches [0029] “the present inventors propose to monitor the phosphorylation status of the serine 472 of the RelB subunit of NFκB in order to i) evaluate if the RelB-dependent NFκB pathway is activated in a sample (whatever the stimulus of this activation is), ii) assess the migratory capacity of cells present in a sample, iii) prognose the clinical outcome of a disease involving undesired cell migration.
As to claim 2, Baud et al. teach [0050] detecting the phosphorylated RelB protein of SEQ ID NO:1 at serine residue 472 using an antibody or fragment thereof.
As to claim 3 and 5, Baud et al teach [0089] that detection with the antibody may occur in the cytoplasm or nucleus.
As to claim 6-7, Baud et al teach [0018, 0213-0214] that metastatic breast cancer cells exhibit RelB serine-472 phosphorylation that is not detectable in non-metastatic breast cancer cells which would be “indicative of a poor prognosis” in a subject. A poor prognosis would inherently comprise a significant increase of the risk for the occurrence of metastases for a subject and or a significant decrease of overall survival expectancy.
As to claim 9, 15-16, and 19, Baud et al. teach [0213] that they performed immunoblotting analysis of 6 triple-negative basal-like highly invasive breast cancer cell lines vs 3 luminal A/B non-metastatic breast cancer cells using anti-phospho serine-472 specific RelB antibody. The reference further teaches [0183] “two hybridomas” out of thirty entered the cloning phase and the two best subclones were selected for purification. Absent evidence to the contrary, the anti-phospho serine-472 specific RelB antibody used by the inventors inherently comprised at least one CDR sequence selected from SEQ ID NOs:6-11 or a functionally-conservative variant thereof. As further evidence, prosecution of related application 15/817868 indicates (applicant’s arguments of 04/20/2021) that “The specification in the paragraph at page 41, lines 11-21, describes production of two hybridomas and the monoclonal antibodies produced by them. The specification has been amended to add the laboratory name of one of the hybridomas. A deposit of the hybridoma has been made and the deposit information has also been added. This hybridoma was described in the application as filed and the antibody produced by it was described. Accordingly, this amendment does not add new matter.” Baud et al. further teach [0098] kits comprising the monoclonal antibodies that have been generated by the inventors in order to detect specifically the phosphorylation level of serine 472 of the RelB protein.
As to claims 10-11, 13, 17-18, Baud et al. teach [0134] detecting cancer wherein the subject is suffering from solid cancers such as lung, breast, prostate, and cervical cancer and wherein the subject is a mammal [0131].
As to claim 12, wherein “the subject is free of metastasis”, one reasonable interpretation is that the subject (of Claim 1) is afflicted with a solid cancer that has yet to spread to other organs and thus the clinician may be assessing the risk of metastasis based on the phosphorylation status. Here, Baud et al. teach [0130] the present invention includes identifying a cancer at risk of metastases in a subject, the said method comprising the steps of: a) detecting the activation of the RelB-dependent NFκB pathway in the cancer cells present in a biological sample of said subject, according to the detecting methods of the invention, andb) concluding that said subject suffers from a cancer at risk of metastases if the RelB-dependent NFκB pathway in said cancer cells is activated.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 4, 8, and 14 is/are also rejected under 35 U.S.C. 103 as being unpatentable over US20180156819 (Baud et al. June 7, 2018) in combination with the teachings of Carvajal-Hausdorf et al. (Laboratory Investigation, 95, 2015)
Baud et al. teaches as set forth above and as applied to claims 1-3, 6-7, 9-13, and 15-19.
With regard to cytoplasmic labeling of the detected phosphorylated RelB protein, Baud et al. does not discuss further quantifying said labeling such as when the labeling is “diffuse” quantifying the intensity or the percentage of cells that are labelled or the percentage of tissue biopsy that is labelled, or when the labeling is “discrete” such that dots are observed and further quantifying either the size or number of dots in cells or the percentage of the surface of the cancer cell sample that is labelled by the dots (Claim 4); or wherein detection of discrete labelling with dots in the cytoplasm is indicative of an increased risk of suffering from cancer (or breast cancer) with a high proliferation potential and/or sensitivity to chemotherapy for the subject (Claims 8 and 14).
With regard to detection and quantifying of phosphorylated RelB protein, Baud et al. teach [0050] that the detection of serine 472 phosphorylation can be achieved with usual immunoassay techniques, such as immunoprecipitations, Western blotting, ELISAs, other sandwich assays, FACS analysis and cross-linking assays, and any other means known to the person of skills in the art. Specific reagents can be used to detect and/or quantify the phosphorylated RelB protein, and to determine the distinct amounts of the phosphorylated and non-phosphorylated forms. For example, the phosphorylated and the non-phosphorylated forms of the RelB protein can be identified on the basis of their respective different electrophoresis mobility by Western blotting with an antibody against RelB or with antibodies recognizing specifically the Ser472-phosphorylated RelB protein. Alternatively, the total amount of phosphorylated RelB protein can be assessed by ELISA with antibodies recognizing specifically the Ser472-phosphorylated RelB protein.
Carvajal-Hausdorf et al. review the quantitative measurement of cancer tissue biomarkers. Regarding measurement of cancer biomarkers, the authors teach (page 387, last para) that in the clinical setting, most pathology laboratories perform in situ protein detection using single-marker chromogenic IHC (immunohistochemistry) with primary monoclonal antibodies and secondary antibodies conjugated with polymer-based amplification systems. Typically, diverse areas from one slide are evaluated and a trained observer (eg, a pathologist or researcher) renders an integrated categorical estimation of results. This approach has become the pathology standard because of its simplicity, low cost (eg, requires only a traditional light microscope), and preservation of contextual morphological information. Typically, the presence of the protein of interest is evaluated in strict correlation with the cell type and compartment where it is detected. The markers are interpreted in a binary manner as present or absent that supports (and/or rules out) a determinate diagnosis.
One of ordinary skill in the art at the time of filing would consider it prima facie obvious to further analyze and quantify the cytoplasmic labeling of the phosphorylated RelB protein according to the routine laboratory techniques as discussed by Baud et al. and Carvajal-Hausdorf et al. because Baud et al. had already distinguished the RelB protein as a putative cancer marker where they observed that “highly invasive basal-like breast cancer cells exhibit the highest level of RelB serine-472 phosphorylation” and that RelB Serine-472 phosphorylation promotes invasion of breast cancer cells. It would be no more than routine to quantify the intensity of the label or the percentage of cells that are labelled or the percentage of tissue biopsy that is labelled as such immunopathological techniques are “typical” according to Carvajal-Hausdorf et al. Further, the observation of dots or dot intensity relative to an increased risk of suffering from cancer (or breast cancer) would be an obvious way to quantify the proliferation potential because the trained pathologist typically interprets the markers in a binary manner. Thus, all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would yield nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 6-7, 10-13, 15-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 11067585. Although the claims at issue are not identical, they are not patentably distinct from each other because the pending claims are generic to the patented claims drawn to an antibody that binds phosphorylated RelB and to the methods of detection of phosphorylated RelB at serine 472.
For example, pending claims 1-2 are drawn to an in-vitro method for classifying a subject afflicted with a solid cancer as having a good or poor prognosis “comprising detecting in a cancer cell sample from the subject phosphorylated RelB protein of SEQ ID NO:1 at the serine residue 472 and/or detecting a RelB homolog phosphorylated at a corresponding serine”. Similarly, the patented claim is broadly drawn to:
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Also, the product of pending claim 15 is generically drawn to a kit comprising an antibody or fragment thereof which binds the phosphorylated RelB protein of SEQ ID NO:1 at the serine residue 472 or to its homolog. This anticipates patented claim 1 drawn to:
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Claims 1-2, 10-13, 16-18 are further rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, and 8 of U.S. Patent No. 9851363. Although the claims at issue are not identical, they are not patentably distinct from each other because both the pending claims and the patented claims are drawn to overlapping subject matter.
For example, Claims 1-4 of the patented claims are broadly drawn to simply detecting phosphorylated serine 472 of the RelB protein:
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This is nearly identical to the active steps of Claims 1-2 of the pending claims. Further, while it appears that US Patent 9851363 may be expired:
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-such an indication of expiration does not foreclose the requirement to provide for a terminal disclaimer because it’s possible that applicants may revive the expired patent. See 37 CFR 1.378.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY B NICKOL, Ph.D. whose telephone number is (571)272-0835. The examiner can normally be reached M-F 9AM-5:30PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/GARY B NICKOL/Primary Examiner, Art Unit 1643