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 .
Claim Status
Claims 3, 5, 7, and 9-11 are currently pending.
WITHDRAWN GROUNDS OF OBJECTION AND/OR REJECTION
Applicant’s arguments, see Remarks, filed January 13, 2025, with respect to
objection to specification at para 55 (see Remarks on pg. 9, part II),
rejection of claims 3-9 under 35 U.S.C. § 112(b) in view of claim amendments (see also Remarks on pg. 10 part IV bridging pg. 11),
rejection of claims 4, 6, and 8 under 35 U.S.C. § 112(d) (see Remarks on pg. 11, part V.),
rejection of claims 3-9 under 35 U.S.C. § 112(a) (see Remarks on pg. 11, part VI through pg. 13),
rejection of claims 1-2 under 35 U.S.C. § 101 (see Remarks on pg. 13, part VII),
rejection of claims 1-4 under 35 U.S.C. 102(a)(1) and/or 102(a)(2) in view of claim amendments (see also Remarks on pg. 13 part VIII bridging pg. 14),
rejection under 35 U.S.C. § 103 of claims 1-9 over De Villiers-zur Hausen ‘018 published July 2017 in view of Yang and claims 1-4 over Bund ‘580 filed November 2018 in view of De Villiers-zur Hausen ‘018 published July 2017, and claims 1-9 over Bund ‘580 filed November 2018 in view of De Villiers-zur Hausen ‘018 published July 2017 further in view of Yang in view of claim amendments (see also Remarks on pg. 14 IX through pg. 18), and
nonstatutory double patenting rejection as applied to claims 1-2 over Pat. No. 11,718,662, claims 1-9 over App. No. 17/444,765, claims 1-2 over App. No.18/335,440, claim 1 over App. No. 16/939,154, and claims 1-9 over App. No. 17/242,116, in view of claim amendments.
have been fully considered and are persuasive. The aforementioned grounds of objection and/or rejection have been withdrawn.
In the “Request for Interview” filed January 13, 2025 applicant’s representative states: "If any issue remains as an impediment to allowance, an interview with the undersigned is respectfully requested, prior to issuance of any paper other than a Notice of Allowance; and, the Examiner is respectfully requested to contact the undersigned to arrange a mutually convenient time and manner for such an interview.”
Applicant's request for an interview at this time is respectfully denied because the specification objection, maintained prior art rejection(s) under 35 U.S.C. § 103, maintained NSDP rejection(s), and new issue(s) raised by amendments, as detailed below, remain as impediments to allowance and it is not clear from applicant’s arguments and amendments of January 13, 2025 how having an interview at this time would result in expediting the case to allowance. (see MPEP 713.01). Due to time constraints and in the interest of compact prosecution an Office Action has been issued. If Applicant would like to schedule an interview please reach out to the examiner before filing a response.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Specification
Maintained
According to 37 CFR 1.71(a), the specification must be written in “full, clear, concise and exact terms”. The disclosure is objected to because of the following informalities:
At para 54 on pg. 14, SEQ ID NO: 3 is described as amino acids 198-217 of SEQ ID NO: 1. However, SEQ ID NO: 3 is not amino acids 198-217 of SEQ ID NO: 1. Alignment shown below.
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Applicant's arguments filed January 13, 2025 have been fully considered but they are not persuasive (see pg. 9, part II). Applicant argues that the specification paragraphs are amended to correctly identify the sequence positions in SEQ ID NO: 1 that correspond to SEQ ID NO: 3. SEQ ID NO: 3 has been amended in the sequence listing as KQINEHTDITASYEQHKKGRT. Only paragraphs 49 and 53 were amended in the submission filed January 13, 2025. Even if paragraph 55 was amended to recite that SEQ ID NO: 2 is amino acids 196-216, the objection to the specification is not overcome. The reason is that the most C-terminal residue of SEQ ID NO: 3 is threonine, whereas position 216 of SEQ ID NO: 1 is valine. See annotations to alignment above.
New Grounds Necessitated by Amendment
Paragraph 49 of the instant specification formerly recited: "Anti-Rep antibodies are preferably, raised (generated) against a Rep protein having the amino acid sequence of…". Amendments to para introduce the text: “In certain embodiments anti-Rep antibodies are used in the methods of the invention which are capable of binding several or all kinds of Rep proteins… SEQ ID NO: 3 (amino acids 196-216 of SEQ ID NO: 1)… derived from the conserved N-terminal Rep protein region from amino acids 1 to 229 of SEQ ID NO: 1." However, this contradicts paragraph 50 which recites: “In certain embodiments anti-Rep antibodies are used in the methods of the invention which are capable of binding several or all kinds of Rep proteins… SEQ ID NO: 3 (amino acids 197-216 of SEQ ID NO: 1)… derived from the conserved N-terminal Rep protein region from amino acids 1 to 229 of SEQ ID NO: 1."
Similarly, paragraph 53 of the specification formerly recited “Examples of such groups of anti-Rep antibodies are shown in Table 1[.]” However, amendments introduce “Anti-Rep antibodies of group A have an epitope… SEQ ID NO: 3 (aa 196-216 of SEQ ID NO:1)… which was employed in the examples as group A antibody.” This contradicts both paragraph 50, as stated above, and paragraph 54 which has not been amended to recite “SEQ ID NO:3 (aa 196-216 of SEQ ID NO: 1)[.]”
Claim Objections
New Grounds Necessitated by Amendment
Claim 3 is objected to because of the following informalities: claim 3 in lines 7 and 8 recites “Ab3-6” which should be “Ab 3-6.” “DSM ACC 3329” should be “DSM ACC3329.” “[P]resent in the sample, and a diagnosis of breast cancer a diagnosis of breast cancer…” is grammatically clarified by “present in a sample and a diagnosis of breast cancer[.]” Appropriate correction is required.
Claim Interpretation
As previously set forth on pg. 3 of the Office Action mailed on September 12, 2024, BMMF1 is a genus of virus-like single stranded circular DNA encoding a Rep protein (see also para 11-16 on pgs. 3-5 and para 31 on pg. 8 of the specification), to which the species MSBI1, MSBI2, CMI1, CMI2, and CMI3 belong (see previously filed claim 2’s dependency from claim 1). Particularly, 7 breast cancer tissue samples contain BMMF1 Rep targets (pg. 3, para 12) of which MSBI1, MSBI2, CMI1, CMI2, and CMI3 represent biomarkers for cancer found in breast tissue (pg. 5, para 16). The art of record confirms the interpretation that MSBI1, MSBI2, CMI1, CMI2, and CMI3 Rep proteins are species belonging to the genus BMMF1 (zur Hausen. Curr Topics in Microbiol and Immunol. March 28 2017. 407:83-116, as cited in the IDS; see particularly Fig. 3 on pg. 95). As set forth in zur Hausen 2017, BMMF1 comprises the following species that are recited in the instant specification: CMI1.252, CMI2.234, CMI3.168, MSBI1.176, and MSBI2.116, which are designated in the instant specification as CMI1, CMI2, CMI3, MSBI1, and MSBI2, respectively (see pg. 5 paragraphs 14 and 15). Additionally, antibody Ab 3-6 (a name for antibody MSBI1 381-6-2 according to the biological deposit DSM ACC3329) is specific for MSBI1 (see Table 1 on pg. 13 and para 56 on pg. 14), and has specificity for the variable C-terminal region of SEQ ID NO: 1 (aa 234-324) which is unique to MSBI1.176 with little homology to any known protein (pg. 8, para 31 and pg. 14, para 56). One of ordinary skill in the art at the time of instant filing would recognize, in view of the foregoing, that detection of BMMF1 with Ab 3-6, deposited as DSM ACC3329, results in detection of MSBI1.
Claim Rejections - 35 USC § 112
New Grounds Necessitated by Amendment
Claims 3, 5, 7, and 9-11 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.
The use of parentheses, “(DSM ACC 3329),” in amendments to claim 3 renders the claim indefinite because it is unclear whether DSM ACC3329 limits Ab 3-6 to the structure of the biological deposit or exemplifies the structure of an antibodies named Ab 3-6. See MPEP § 2173.05(d). Suggested language to clarify the claim includes “Ab 3-6 according to the biological deposit DSM ACC3329,” or “Ab3-6 which has been deposited as DSM ACC3329,” or “Ab 3-6 deposited as DSM ACC3329.”
“[D]etecting whether a... BMMF1 Rep protein is present in a sample” (claim 3 in lines 3-4) indicates to the skilled artisan that one may determine a sample as positive or negative to satisfy the limitations of claim 3. However, in line 8, the step of “detecting binding between BMMF1 Rep protein and antibody Ab 3-6” indicates that the claim is limited to performing the method until achieving positive identification of a sample having a BMMF1 Rep protein bound by Ab 3-6. Since detection as in lines 3-4 may have a different outcome than detection as in line 8, one of ordinary skill would also be unclear as to whether claim 3 as a whole is limited to positive detection of the BMMF1 Rep protein bound by Ab 3-6 or whether the method includes only determining a sample as negative for a BMMF1 Rep protein that Ab 3-6 binds. In other words, would a skilled artisan practicing the method infringe only if a BMMF1 Rep protein positive sample is detected or would determining a sample as negative for a BMMF1 Rep protein by applying Ab 3-6 also infringe?
To advance prosecution, the scope of claim 3 is interpreted as not being limited to only positive detection of a BMMF1 Rep protein by Ab 3-6.
Claims 3, 5, 7, and 9-11 are rejected by virtue of their dependency.
Claim Rejections - 35 USC § 103
New Grounds Necessitated by Amendment
Amendments to the claims limit the scope of the subject to a human subject, and recite contacting a sample from the subject with antibody Ab 3-6 according to DSM ACC3329, and detecting binding the antibody and BMMF1 Rep protein. Claims 10 and 11 are new and recite that the BMMF1 Rep protein comprises at least 20 contiguous amino acids of SEQ ID NO: 1.
Applicant's arguments filed January 13, 2025 have been fully considered but they are not persuasive as it applies the rejection below.
Applicant alleges that “even if the cited documents or combination thereof were to teach all features of the claims, which, it is respectfully asserted is not the case, the claimed invention would still be nonobvious.” (Remarks, last sentence of para bridging pg. 15 and 16). Particularly, Applicant cites that all elements of the claims must be shown in the art, whereas common sense and basic knowledge alone cannot establish the presence of an element, and that there must be reason to combine elements. (Remarks, pg. 15, para 7 and last para bridging pg. 16). In further arguments, Applicant alleges that a reasonable expectation of success has not been shown whereas there must be motivation to combine references and reasonable expectation of success presented by the Examiner. (pg. 16, 2nd full para). On pg. 17 in the 2nd para Applicant states that cited case law directed to unexpected results foreshadows the discussion on the rejections applied and thus the invention is clearly patentable over the cited art.
Although Applicant alludes to unexpected results (pg. 17, 2nd para), no further reasoning or evidence is provided. Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). (MPEP 2145 I.). Thus, without evidence or reasoning supporting an statement of unexpected results, the presented statement is mere attorney argument and is not sufficient to overcome the prima facie case(s) of obviousness.
Claims 3 stands and claim 10 are rejected under 35 U.S.C. 103 as being unpatentable over Zur Hausen et al. WO 2018/069296 A1 published on April 19, 2018 (hereinafter ‘296), and further in view of De Villiers-zur Hausen et al. in US 2017/0198018 published on July 13, 2017 (hereinafter ‘018).
The applied reference (‘296) has a common inventors (Zur Hausen, Harald; Bund, Timo) and assignee (Deutsches Krebsforschungszentrum Dtiftung Des Offentlichen Rechts) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Applicant argues that not all claimed limitations are supplied by the prior art and that common sense, without evidence or reasoning, cannot supply a missing limitation. Examiner respectfully asserts that the references teach each and every limitation of the instant invention without invoking common sense to supply limitations.
On pg. 2 in the 2nd full para, ‘296 teaches that MSBI1 is expressed in human cells and generically states that MSBI1 is a biomarker for pathogenicity screening assays and teaches that the detection and quantification methods are for use in the diagnosis of a neurodegenerative disease (pg. 1, 1st para). Note well, MSBI1 is a species within the genus of BMMF1 Rep proteins (see discussion on pg.3 of Office Action mailed September 12, 2024 and in the rejections under 35 U.S.C. 112(b) above) and therefore teaches the limitations of the instant claims with respect to a BMMF1 Rep protein. "A generic claim cannot be allowed to an applicant if the prior art discloses a species falling within the claimed genus." The species in that case will anticipate the genus. In re Slayter, 276 F.2d 408, 411, 125 USPQ 345, 347 (CCPA 1960); In re Gosteli, 872 F.2d 1008, 10 USPQ2d 1614 (Fed. Cir. 1989). (See MPEP 2131.02).
On pg. 17, in the first and second full paras, ‘296 teaches detecting “Rep protein,” which has the scope of CMI1, CMI2, CMI3, MSBI1, and/or MSBI2 (see pg. 9, last para), in a sample by anti-Rep antibodies. On pg. 20, ‘296 teaches, inter alia, MSBI1 may be specifically detected by antibody MSBI1 381-6-2 according to DSM ACC3329 (see last para and Table 1). Antibody MSBI1 381-6-2 specifically detects a structural epitope of MSBI1 according to SEQ ID NO: 1. (pg. 21, 3rd para).
Example 7 of ‘296 teaches that human embryonic kidney cells, HEK293T, were transfected to express MSBI1 and incubated with anti-Rep antibodies. Incubating with an antibody teaches the limitation of contacting with an antibody because to incubate with an antibody the antibody is applied under conditions that allow the antibody to contact its cognate antigen. Specifically, the antibodies include group C antibodies, which according to Table 1, is limited the MSBI1 381-6-2 antibody.
Claim 14 of ‘296 teaches detecting the amount of Rep protein according to SEQ ID NO: 1 by antibodies that bind to an epitope comprised by anti-Rep antibodies that bind to an epitope of SEQ ID NO: 1 amino acids 230-324 and correlating an at least 2-fold increased amount of Rep protein compared to a control sample with a diagnosis of MS.
The MSBI1 sequence, SEQ ID NO: 1, of ‘296 is identical to instant SEQ ID NO: 1, as shown by the alignment below.
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Thus ‘296’s statement that antibody MSB1 28-6-2 binds to MSBI according to SEQ ID NO: 1 teaches limitations pertinent to claim 10.
While ‘296 teaches detecting MSBI1 with the DSM ACC3329 antibody in the sample of a sample of a subject in the context of diagnosis, ‘296 does not teach providing a diagnosis or predisposition for breast cancer in a subject.
However, ‘018 teaches that the intended purpose of antibodies binding to the MSBI1.176 Rep protein is, inter alia, for diagnosis of breast cancer (see, e.g., claims 8 and 9). Regarding human subjects, ‘018 teaches that MSBI1.176 and other Rep proteins replicate in human cells and are identified as latent in normal brains and active in the brains of human patients with multiple sclerosis (pg. 4, para 86 and para 96). MSBI Rep proteins were isolated from the post mortem brain tissue of patients with multiple sclerosis, whereas CMI was first isolated from cow milk (pg. 1, para 3; see also Example 2). Regarding antibodies, ‘018 teaches that antibodies are made from an antigen containing a polypeptide of, inter alia, MSBI (pg. 7, para 143). ‘018 teaches that a biological sample is contacted for the presence of MSBI polypeptide or anti-MSBI antibody and detecting the immunological complex formed between the antibody and said polypeptide, i.e. detecting binding of antibody to the MSBI polypeptide. On pg. 8, in para 157, ‘018 teaches avoiding assay formats that denature conformational epitopes and a common features of the assays is the conditions that allow for antigen to bind to antibodies.
Expounding on the statement that ‘018 teaches antibodies binding to MSBI1.176/MSBI1 is, among other things, for the diagnosis of breast cancer, the problem that ‘018 addresses is the identification of infectious nucleotide sequences that are associated with disease including cancer and diseases of the central nervous system (pg. 1, para 7). On pg. 1, in para 10, ‘018 teaches “it is reasonable to assume that the viral sequences [e.g. MSBI] might be associated with the development of diseases like cancer, specifically colon and breast cancers, but also...” multiple sclerosis, amyotrophic lateral sclerosis Parkinson’s, and Alzheimer’s disease, i.e. species of neurodegenerative disease (pg. 1, para 10; emphasis added). Claims 8 and 9 are directed to diagnosing breast cancer or the aforementioned neurodegenerative diseases
Applicant alleges that no motivation to combine or reasonable expectation of success has been made. Examiner disagrees for the reasons below.
In the context of ‘296, the skilled artisan would particularly have been motivated to detect MSBI proteins because MSBI1 and MSBI2 were identified from the brain tissue of patients with multiple sclerosis (pg. 1, last para). Given that the two MSBI Rep proteins were isolated from human patients, whereas the CMI Rep proteins were originally identified in cow milk, the person of ordinary skill in the art would have reasonably expected that MSBI in particular is a Rep protein that has the ability to infiltrate, infect, and replicate in human cells. Thus one of skill would have been motivated to select an MSBI protein as a diagnostic marker in human subjects from the listed Rep proteins of ‘296 and ‘018. Between MSBI1 and MSBI2, one of ordinary skill would have found specific detection of MSBI1 with an antibody as obvious over MSBI2 because the only antibodies specific for an MSBI Rep protein at the time of instant filing were specific for only MSBI1 (‘296, pg. 20, Table 1). Furthermore, MSBI1 381-6-2 is one of only 3 antibodies specific for an MSBI Rep protein known in the art.
Both ‘296 and ‘018 teach the detection steps of incubating / contacting a sample with an antibody that binds to a Rep protein and detecting an immunological complex / binding of the antibody to the Rep protein, thereby diagnosing / indicating a particular disease. In the ‘018 reference both neurodegenerative diseases and breast cancer may be diagnosed. The person of ordinary skill in the art, would therefore have found it obvious to extend the use of the method steps for detecting Rep proteins, particularly MSBI1 as discussed above, in the context of neurodegenerative disease as taught by ‘296, to the context of diagnosing breast cancer as taught by ‘018.
A person of ordinary skill in the art would have found it obvious to use the detection step of ‘296 for the purpose of diagnosing breast cancer, as taught by ‘018. The skilled artisan would have been motivated by ‘018’s teaching that the intended purpose of the antibodies binding to MSBI1 is for diagnosis of breast cancer as well as Multiple sclerosis. The skilled artisan would have had a reasonable expectation of success because ‘018 explicitly discloses the operable purpose of anti-MSBI1 antibodies. More specifically, ‘018 states from the perspective of one skilled in the art that it would be reasonable to expect an association between the presence of Rep proteins, including MSBI1, with cancer, particularly breast cancer.
In response to applicant’s argument that ‘296 is nonanalogous art, see pg. 18 in part C. of Remarks, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). A reference can be analogous if it is in same field of endeavor as the claimed invention even if it addresses a different problem. (MPEP 2141.01(a) I.). The difference between ‘296 and the instant invention is that ‘296 addresses a different problem, neurodegenerative disease, than the instant application, breast cancer. However, both the instant invention and ‘296 are in the same field of endeavor because they describe methods of detecting Rep proteins, including CMI1, CMI2, CMI3, MSBI1, and MSBI2, for a diagnostic purpose. Searching the detection steps of one would lead to the other. Therefore, ‘296 is analogous art.
Applicant alleges on pg. 18 in part C that there is no teaching or suggestion to apply techniques used in detecting neurodegenerative disorders for breast cancer diagnosis. However, ‘018 teaches the techniques that ‘296 uses for detecting neurodegenerative disorders, i.e. contacting a biological sample with antibodies and detecting the antibody-Rep protein complex (‘018 claim 12 and ‘296 claim 13 and 14), and ‘018 teaches that a diagnostic composition comprising antibodies to MSBI1, e.g., are used for diagnosing breast cancer and the neurodegenerative disease multiple sclerosis, amyotrophic lateral sclerosis, transmissible spongiform encephalopathies, Parkinson’s, or Alzheimer’s disease (claim 9). Therefore, Examiner respectfully disagrees because there are explicit teachings and suggestions in ‘018 to use ‘296’s techniques for neurodegenerative disorders to diagnose breast cancer.
In conclusion, when Applicant’s arguments are taken as a whole and weighed against the evidence supporting the prima facie case of unpatentability, the instant claims, by a preponderance of evidence, remain unpatentable. See M.P.E.P. § 716.01(d).
Claims 3, 5, 7, and 9 stand and claims 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Zur Hausen et al. WO 2018/069296 A1 published on April 19, 2018 (hereinafter ‘296) in view of De Villiers-zur Hausen et al. in US 2017/0198018 published on July 13, 2017 (hereinafter ‘018); as applied to claims 3 and 10 above and further in view of Yang et al. Int J Clin Pathol. 2015. 8(6):6656-6664.
The applied reference (‘296) has a common inventors (Zur Hausen, Harald; Bund, Timo) and assignee (Deutsches Krebsforschungszentrum Dtiftung Des Offentlichen Rechts) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Applicant argues that not all claimed limitations are supplied by the prior art and that common sense, without evidence or reasoning, cannot supply a missing limitation. Examiner respectfully asserts that the references teach each and every limitation of the instant invention without invoking common sense to supply limitations.
See discussion above on ‘296 in view of ‘018 as applied to claims 3 and 10 above.
While ‘296 in view of ‘018 teaches a method for providing a diagnosis of or determining a predisposition for breast cancer by contact a sample from a human subject with Ab 3-6 and detecting binding to a BMMF1 Rep protein, ‘296 in view of ‘018 does not teach the tissue is cancerous breast tissue or additionally detecting CD68 positive cells in the sample.
However, Yang et al. teaches detecting CD68 with an anti-CD68 antibody in human malignant breast tissue (see pg. 6657, “Tissue samples”, and “Immunohistochemistry and antibodies”). Yang et al. teaches that CD68 expression is a marker for tumor associated macrophages (TAMs) which increase along with tumor stage and size (pg. 6660, Table 2, right col. last para). Additionally, CD68 positive TAMs are prognostic for breast cancer survival (pg. 6660, Fig. 3).
Applicant alleges that no motivation to combine or reasonable expectation of success has been made. Examiner disagrees for the reasons below.
It would have been prima facie obvious to a) apply the Ab2-3 antibody to cancerous breast tissue for the purpose of diagnosing breast cancer and b) additionally detect CD68 positive cells with an anti-CD68 antibody. The disclosure of ‘296 in view of ‘018 is sufficient to make a prima facie case for applying the Ab2-3 antibody to cancerous breast tissue because ‘296 in view of ‘018 discloses that said antibody is useful for diagnosing breast cancer, which is routinely determined by biopsy of breast tissue. Applying anti-Rep antibodies to cancerous breast tissue would amount to no more than using anti-Rep antibodies for their intended purpose with methods that are routine to the art. Additionally and/or alternatively, Yang et al. teaches that CD68 positive cells can be used to determine severity of cancer and prognosis for survival, and are detectable by applying anti-CD68 antibodies to cancerous breast tissue samples. Therefore, the skilled artisan would have been motivated by the apparent advantage that detection of CD68 positive cells has in determining stage of disease. The expectation of some advantage is the strongest rationale for combining references (MPEP 2144(II)). The skilled artisan would have had an expectation of success in combining the method diagnosing breast cancer by detecting Rep protein with an anti-Rep antibody with the method of Yang et al. on clinical staging of breast cancer by detecting CD68 positive cells in cancerous breast tissue biopsies, because each method individually is expressly taught in the prior art, which are presumed as operable (see MPEP 2121 (I)), and combining the two methods would provide the advantage of clinically staging disease and providing prognosis for survival.
Regarding the combination of references with Yang (see Remarks, pg. 17, part B. last para bridging pg. 18), Applicant argues that Yang teaches CD68-positive cells are a prognostic and not diagnostic marker, and CD68 itself is not a marker specific to breast cancer. However, the breadth of the claims allows for the use of prognostic markers in additional to diagnostic markers. Additionally, as taught by Yang, when CD68 staining is applied to a malignant breast tissue, the results are indicative of and specific to the nature of the breast cancer. As discussed above, there would have been an advantage in using CD68 as a prognostic marker in combination with the diagnostic method of ‘296 in view of ‘018 because practitioners would be able to inform a patient on the clinical stage and prognosis of the breast cancer in addition to confirming that the subject is properly diagnosed with breast cancer. This would be of particular advantage because different therapeutic approaches are used for patients with different stages and prognoses of breast cancer.
Applicant argues that “the value of CD68+ detection is only achieved when combined with BMMF1 detection for a specific case-vs-control detection tool as shown in the present application.” However, Yang provides evidence to the contrary because CD68+ detection has value in determining clinical stage and prognosis of disease. Therefore, the use of CD68+ and the reason and motivation behind the obviousness of the claimed method extends beyond what Applicant has described. “The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991) (discussed below).” (See MPEP 2144 IV.).
In conclusion, when Applicant’s arguments are taken as a whole and weighed against the evidence supporting the prima facie case of unpatentability, the instant claims, by a preponderance of evidence, remain unpatentable. See M.P.E.P. § 716.01(d).
Claims 3 and 7 stand and claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Bund et al. US 2021/0003575 A1 effectively filed on January 25, 2019 (hereinafter ‘575) and further in view of De Villiers-zur Hausen et al. in US 2017/0198018 published on July 13, 2017 (hereinafter ‘018).
The applied reference (‘575) has a common inventors (Bund, Timo; Zur Hausen, Harald) and assignee (Deutsches Krebsforschungszentrum Dtiftung Des Offentlichen Rechts) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Applicant argues that not all claimed limitations are supplied by the prior art and that common sense, without evidence or reasoning, cannot supply a missing limitation. Particularly, ‘575 in combination with ‘018 fails to teach or suggest a BMMF1 DNA-replication-associated protein using antibody Ab 3-6 for diagnosis of breast cancer (pg. 18, part E). Examiner respectfully asserts that the references teach each and every limitation of the instant invention without invoking common sense to supply limitations.
‘575 teaches that MSBI1 Rep protein is expressed in human cells (pg. 4, para 50), and that the subject is preferably a human patient (pg. 5, para 52). As discussed above, MSBI1 is a species within the genus of BMMF1 Rep proteins.
In Example 1, colon tissue samples from a subject were incubated with four antibodies, 10-3, 3-6, 11-5, and 1-5 and detection of binding was determined by colorimetric staining. (see pg. 6, para 76), all of which are specific for MSBI1 except antibody 1-5 (see Table 1 on pg. 6). On pg. 5, in para 62, “anti-Rep antibodies are used for the detection… of Rep protein in the sample.” The claims of ’575 are also directed to detecting Rep proteins, including MSBI1, in a sample from a subject by anti-Rep antibodies. Claim 4 in particular includes detection via anti-Rep antibodies that binding within amino acids 230-324 of SEQ ID NO: 1. Examples of anti-Rep antibodies included Ab 3-6, which is MSBI1 specific and recognizes an epitope in amino acids 137-324 of SEQ ID NO: 1. (pg. 6, Table 1 and para 72).
The MSBI1 SEQ ID NO: 1 of ‘575 is identical to instant SEQ ID NO: 1, as shown by the alignment below.
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In claims 7-10, ‘575 teaches additionally detecting CD68 in a sample by an anti-CD68 antibody, teaching limitations of instant claims 7 (see also pg. 2, para 13 and 15; “the regions with highest Rep specific antibody detection correlate with regions with highest detection levels for CD68 positive cells pointing towards a localization of the Rep-specific antigens in inflammatory islands”).
While ‘575 teaches detecting MSBI1 in a sample from a subject by incubating said sample with Ab 3-6, ‘575 does not teach providing a diagnosis or determining a predisposition for breast cancer in a subject.
However, ‘018 teaches that the intended purpose of antibodies binding to the MSBI1.176 Rep protein is, inter alia, for diagnosis of breast cancer (see, e.g., claims 8 and 9). Regarding human subjects, ‘018 teaches that MSBI1.176 and other Rep proteins replicate in human cells and are identified as latent in normal brains and active in the brains of human patients with multiple sclerosis (pg. 4, para 86 and para 96). MSBI Rep proteins were isolated from the post mortem brain tissue of patients with multiple sclerosis, whereas CMI was first isolated from cow milk (pg. 1, para 3; see also Example 2). Regarding antibodies, ‘018 teaches that antibodies are made from an antigen containing a polypeptide of, inter alia, MSBI (pg. 7, para 143). ‘018 teaches that a biological sample is contacted for the presence of MSBI polypeptide or anti-MSBI antibody and detecting the immunological complex formed between the antibody and said polypeptide, i.e. detecting binding of antibody to the MSBI polypeptide. On pg. 8, in para 157, ‘018 teaches avoiding assay formats that denature conformational epitopes and a common features of the assays is the conditions that allow for antigen to bind to antibodies.
Expounding on the statement that ‘018 teaches antibodies binding to MSBI1.176/MSBI1 is, among other things, for the diagnosis of breast cancer, on pg. 1, in para 10, ‘018 teaches “it is reasonable to assume that the viral sequences [e.g. MSBI] might be associated with the development of diseases like cancer, specifically colon and breast cancers[.](pg. 1, para 10; emphasis added). Claims 8 and 9 are directed to diagnosing breast cancer or colon cancer.
Applicant alleges that no motivation to combine or reasonable expectation of success has been made. Examiner disagrees for the reasons below.
In the context of ‘575, the skilled artisan would particularly have been motivated to detect MSBI1 because three out of the four antibodies used to detect Rep proteins in colon tissue samples were specific for detecting MSBI1. Given that the two MSBI Rep proteins were isolated from human patients, whereas the CMI Rep proteins were originally identified in cow milk, the person of ordinary skill in the art would have reasonably expected that MSBI in particular is a Rep protein that has the ability to infiltrate, infect, and replicate in human cells. Thus one of skill would have been motivated to select an MSBI protein as a diagnostic marker in human subjects from the listed Rep proteins of ‘575 and ‘018. Additionally, ‘575 teaches that a human subject is preferably diagnosed by the described method. Between MSBI1 and MSBI2, one of ordinary skill would have found specific detection of MSBI1 with an antibody as obvious over MSBI2 because the only antibodies for an MSBI Rep protein at the time of instant filing were specifically for MSBI1 (‘296, pg. 20, Table 1). Furthermore, MSBI1 381-6-2 is one of only 3 antibodies specific for an MSBI Rep protein known in the art that are deposited in a repository.
Both ‘575 and ‘018 teach the detection steps of incubating / contacting a sample with an antibody that binds to a Rep protein and detecting an immunological complex / binding of the antibody to the Rep protein, thereby diagnosing / indicating a particular disease. In the ‘018 reference both colorectal and breast cancer may be diagnosed. The person of ordinary skill in the art, would therefore have found it obvious to extend the use of the method steps for detecting Rep proteins, particularly MSBI1 as discussed above, in the context of colorectal as taught by ‘575, to the context of diagnosing breast cancer as taught by ‘018.
A person of ordinary skill in the art would have found it obvious to use the detection step of ‘575 for the purpose of diagnosing breast cancer, as taught by ‘018. The skilled artisan would have been motivated by ‘018’s teaching that the intended purpose of the antibodies binding to MSBI1 is for diagnosis of breast cancer as well as colorectal cancer. The skilled artisan would have had a reasonable expectation of success because ‘018 explicitly discloses the operable purpose of anti-MSBI1 antibodies. More specifically, ‘018 states from the perspective of one skilled in the art that it would be reasonable to expect an association between the presence of Rep proteins, including MSBI1, with colon or breast cancer.
Applicant argues that ‘575 is not prior art because the subject matter disclosed therein was obtained directly or indirectly from the inventor or joint inventor on the application.
However, to invoke the 102(b)(2)(A) exception the applicant may establish by way of an either an affidavit or declaration under 37 CFR 1.130(a) or pre-emptively by a statement regarding inventor-originated disclosures made in a U.S. patent document in the specification upon filing that the subject matter upon which the rejection is based is by another who obtained the subject matter from the inventor or joint inventor (MPEP 2154.02(a) and 2155.03). Since the latter was not made upon filing and an affidavit or declaration under 37 CFR 1.130(a) has not been filed, the argument does not overcome the prima facie case of obviousness.
Applicant also argues that the “‘575 and the present application are commonly owned by Deutsches Krebsforschungszentrum DKFZ.” (see Remarks, pg. 18, part E, 2nd para). However, the exception under 102(b)(2)(C) is made by a clear and conspicuous statement that the claimed invention of the application under examination and the subject matter disclosed in the ‘575 document applied as prior were owned by the same person or subject to an obligation of assignment to the same person not later than the effective filing date of the claimed invention. (see MPEP 2154.02(c)). The presently made statement is not sufficient to overcome the rejection by the 102(b)(2)(C) exception because the common ownership is not clearly and conspicuous stated as being in effect not later than the effective filing date of the claimed invention.
In conclusion, when Applicant’s arguments are taken as a whole and weighed against the evidence supporting the prima facie case of unpatentability, the instant claims, by a preponderance of evidence, remain unpatentable. See M.P.E.P. § 716.01(d).
Claims 3, 5, 7, and 9 stand and claims 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Bund et al. US 2021/0003575 A1 effectively filed on January 25, 2019 (hereinafter ‘575) in view of De Villiers-zur Hausen et al. in US 2017/0198018 published on July 13, 2017 (hereinafter ‘018); as applied to claims 3, 7, and 10 above and further in view of Yang et al. Int J Clin Pathol. 2015. 8(6):6656-6664.
The applied reference (‘575) has a common inventors (Bund, Timo; Zur Hausen, Harald) and assignee (Deutsches Krebsforschungszentrum Dtiftung Des Offentlichen Rechts) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Applicant argues that not all claimed limitations are supplied by the prior art and that common sense, without evidence or reasoning, cannot supply a missing limitation. Examiner respectfully asserts that the references teach each and every limitation of the instant invention without invoking common sense to supply limitations.
See discussion above on ‘575 in view of ‘018 as applied to claims 3, 7, and 10. On pg. 2, in para 16, ‘575 also teaches that the presence and level of Rep proteins hold prognostic value (see also pg. 8, para 92-94).
While ‘575 in view of ‘018 teaches a method for providing a diagnosis of or determining a predisposition for breast cancer by contacting the sample with Ab 3-6 and detecting binding between Ab 3-6 and BMMF1 Rep protein, ‘575 in view of ‘018 does not teach the tissue is cancerous breast tissue or additionally detecting CD68 positive cells in the sample.
However, Yang et al. teaches detecting CD68 with an anti-CD68 antibody in malignant breast tissue (see pg. 6657, “Tissue samples”, and “Immunohistochemistry and antibodies”). Yang et al. teaches that CD68 expression is a marker for tumor associated macrophages (TAMs) which increase along with tumor stage and size (pg. 6660, Table 2, right col. last para). Additionally, CD68 positive TAMs are prognostic for breast cancer survival (pg. 6660, Fig. 3).
Applicant alleges that no motivation to combine or reasonable expectation of success has been made. Examiner disagrees for the reasons below.
It would have been prima facie obvious to a) apply anti-Rep antibodies to cancerous breast tissue for the purpose of diagnosing breast cancer and b) additionally detect CD68 positive cells with an anti-CD68 antibody. The disclosure of ‘575 in view of ‘018 is sufficient to make a prima facie case for applying anti-Rep antibodies to cancerous breast tissue because ‘018 discloses that said antibodies are useful for diagnosing breast cancer, which is routinely determined by biopsy of breast tissue. Applying anti-Rep antibodies to cancerous breast tissue would amount to no more than using anti-Rep antibodies for their intended purpose with methods that are routine to the art. Additionally and/or alternatively, Yang et al. teaches that CD68 positive cells can be used to determine severity of cancer and prognosis for survival, and are detectable by applying anti-CD68 antibodies to cancerous breast tissue samples. Therefore, the skilled artisan would have been motivated by the apparent advantage that detection of CD68 positive cells has in determining stage of disease. The expectation of some advantage is the strongest rationale for combining references (MPEP 2144(II)). The skilled artisan would have had an expectation of success in combining the method diagnosing breast cancer by detecting Rep protein with an anti-Rep antibody with the method of Yang et al. on clinical staging of breast cancer by detecting CD68 positive cells in cancerous breast tissue biopsies, because each method individually is expressly taught in the prior art, which are presumed as operable (see MPEP 2121 (I)), and combining the two methods would provide the advantage of clinically staging disease and providing prognosis for survival.
Regarding the combination of references with Yang (see Remarks, pg. 17, part B. last para bridging pg. 18), Applicant argues that Yang teaches CD68-positive cells are a prognostic and not diagnostic marker, and CD68 itself is not a marker specific to breast cancer. However, the breadth of the claims allows for the use of prognostic markers in additional to diagnostic markers. Additionally, as taught by Yang, when CD68 staining is applied to a malignant breast tissue, the results are indicative of and specific to the nature of the breast cancer. As discussed above, there would have been an advantage in using CD68 as a prognostic marker in combination with the diagnostic method of ‘296 in view of ‘018 because practitioners would be able to inform a patient on the clinical stage and prognosis of the breast cancer in addition to confirming that the subject is properly diagnosed with breast cancer. This would be of particular advantage because different therapeutic approaches are used for patients with different stages and prognoses of breast cancer.
Applicant argues that “the value of CD68+ detection is only achieved when combined with BMMF1 detection for a specific case-vs-control detection tool as shown in the present application.” However, Yang provides evidence to the contrary because CD68+ detection has value in determining clinical stage and prognosis of disease. Therefore, the use of CD68+ and the reason and motivation behind the obviousness of the claimed method extends beyond what Applicant has described. “The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991) (discussed below).” (See MPEP 2144 IV.).
In conclusion, when Applicant’s arguments are taken as a whole and weighed against the evidence supporting the prima facie case of unpatentability, the instant claims, by a preponderance of evidence, remain unpatentable. See M.P.E.P. § 716.01(d).
The standing prior art rejections over ‘296 can be overcome by properly invoking the 102(a)(1)(A) and 102(b)(2)(A) or (b)(2)(C) exceptions. The rejections over ‘575 can be overcome by properly invoking the 102(b)(2)(A) or (b)(2)(C) exceptions.
Double Patenting
New Grounds Necessitated by Amendment
Applicant's arguments filed January 13, 2025 have been fully considered but they are not persuasive. Applicant argues that “[n]o claims of the cited applications teach or suggest a diagnostic method for breast cancer using the specific antibody Ab 3-6[.]” Examiner respectfully disagrees for the reasons discussed below.
Claim 3 stands and claim 10 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-6 of copending Application No. 18/335,440 in view of De Villiers-zur Hausen et al. in US 2017/0198018 published on July 13, 2017 (hereinafter ‘018).
SEQ ID NO: 1 of ‘440 is identical to instant SEQ ID NO: 1, as shown by the alignment below.
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Additionally, ‘440 teaches the step of detecting the amount of Rep protein in a sample from a subject by anti-Rep antibodies for diagno