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
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The present application claims benefit under 35 U.S.C. 119(e) to U.S. Provisional application 63/434,565, filed 12/22/2022.
Election/Restrictions
Applicant’s election without traverse of Group I, encompassing claims 1-10, in the reply filed on 7/29/2026, is acknowledged. Claims 11-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/29/2026. Applicant’s election of species is acknowledged. Applicants elected an “antibody or fragment thereof” as the species of anti-fibrotic agent of claim 7.
Status of Claims
Claims 1-16 are pending; claims 11-16 are withdrawn; claims 1-10 are being examined on the merits.
Claim Objections
Claim 1-4, 6 and 8-9 objected to because of the following informalities: Claims 2-4, 6 and 8-9 recite “pro-N-cadherin”, while claim 1 recites “PNC”. The specifications recite “PNC” as an acronym of pro-N-cadherin (pg. 4, para. 1). If applicants choose to use an acronym, the acronym should be defined on first use and then used in each instance therefrom. Here applicants do not introduce the “PNC” acronym of claim 1, and then don’t use the acronym in the rest of the claims. Appropriate correction is required.
Claim 7 is objected to because of the following informalities: Claim 7 is missing a period at the end of the sentence. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1-10 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.
Regarding claim 1, the phrase "such as" (or “e.g.”) renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). As claims 2-10 depend from claim 1, but fail to rectify the indefiniteness of types of samples that may be assayed, claims 2-10 are also rejected.
Claim 3 is 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.
Regarding claim 3; the term “HC5LC4” is a relative term which renders the claim indefinite. The terms are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically, t for use in the invention. For example, Figure 1A describes 22 different variant species of an antibody, whereby various heavy chains are paired with various light chains (i.e. HC1 LC1). The specifications do not provide the structure of any of the antibodies or the heavy or light chain fragments thereof. Therefore the skilled artisan has no way to determine what an antibody called “HC5LC4” is, or how to determine which antibodies in the art would fall within the scope of the claim.
Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. See MPEP § 2173.05(s). Here, the specific antibody “HC5LC4” should be claimed by its minimal required structure, such as by the amino acid sequences of the anti-PNC binding domain. If the structure is presented in the specifications, then it may be reasonable for the artisan to look to the specifications for description of antibody “HC5LC4”. However, when the specification does not provide any structure to the antibody, it is unclear what the antibody is. For example, it is unclear if the antibody “HC5LC4” is novel to the instant application, whereby it may provide a patentable point of novelty to the invention, or is art-recognized and commonly available for purchase. As the claim is drawn to a relative term, claim 3 is rejected for indefiniteness.
Claim 5 is 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.
Regarding claim 5, the phrase "such as" (or “e.g.”) renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). As this occurs repeatedly, claim 5 is rejected for indefiniteness.
Claim 10 is 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.
Claim 10 is rejected because the therapeutic agents in parentheses are exemplary language, and it is not clear whether the therapeutic agents listed in parentheses are part of the claimed invention. Such language does not further limit the claim but potentially causes confusion over the claim scope. For example, claim 10 recites anti-CCL2 antibody (CNTO 888). Is the claim limited to only CNTO 888, or are alternative anti-CCL2 antibodies encompassed by the claim? MPEP 2173.05(d) states that “description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim.” Therefore, exemplary language should either be positively recited as a claim limitation or removed from the claim altogether.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 3 and 9 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
It is apparent that the hybridoma that produce the “HC5LC4” and “10A10” antibodies are required to practice the claimed invention. As a required element, it must be known and readily available to the public or obtainable by a repeatable method set forth in the specification. Here the specifications do not describe the structure of the HC5LC4 or 10A10 antibodies, or methods of making the antibodies, nor any of the variant antibodies of Figure 1, such that a skilled artisan may “make and use” the antibody in the invention. The specifications describe the 10A10 antibody was generated from the antibody producing hybridoma clone 10A10, which was acquired as a gift (specs., pg. 56, para. 2). As claim 3 recites an antibody against pro-N-cadherin in the assay for “characterizing” a sample as pathological or non-pathological based on the presence of, or location of, pro-N-cadherin, it is necessary to have the anti-pro-N-cadherin antibody to practice the methods. Claim 9 recites the anti-fibrotic therapeutic agent is antibody 10A10 or HC5LC4, and thus requires at least one of the antibodies to practice the methods. Thus, the hybridoma that produces the HC5LC4 antibody and the hybridoma that produces the 10A10 antibody must be made available in order to enable the methods of the invention. If they are not so obtainable or available, the enablement requirements of 35 U.S.C. 112, first paragraph, may be satisfied by a deposit of the pertinent cell lines which produce these antibodies. See 37 CFR 1.801-1.809.
If the deposit has been made under the terms of the Budapest treaty, an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the hybridoma has been deposited under the Budapest Treaty and that the hybridoma will be irrevocably and without restriction or condition released to the public upon the issuance of a patent would satisfy the deposit requirement made herein. See 37 CFR 1.808. Further, the record must be clear that the deposit will be maintained in a public depository for a period of 30 years after the date of deposit or 5 years after the last request for a sample or for the enforceable life of the patent whichever is longer. See 37 CFR 1.806.
If the deposit has not been made under the Budapest treaty, then an affidavit or declaration by Applicants or someone associated with the patent owner who is in position to make such assurances, or statement by an attorney of record over his or her signature, stating that the deposit has been made at an acceptable depository and that the criteria set forth in 37 CFR 1.801-1.809, have been met.
Further, amendment of the specification to disclose the date of deposit and the complete name and address of the depository is required as set forth in 37 C.F.R. 1.809(d). The World Intellectual Property Organization (WIPO) publishes a Guide to the Deposit of Micro-organisms under the Budapest Treaty (WIPO Publication No. 661 (E)) on the procedures and requirements concerning the deposit of biological material, including procedures for obtaining a sample of deposited material, in each of the international depository authorities. The Guide and a list of current IDAs under the Budapest Treaty are available at www.wipo.int/treaties/en/registration/budapest/.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 2, 4 and 6-8 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.
The following quotation from section 2163 of the Manual of Patent Examination
Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions:
The written description requirement for a claimed genus may be satisfied through
sufficient description of a representative number of species by actual reduction to practice... reduction to drawings...or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation
within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed.
Claim 2 recites the method of claim 1 wherein the assay comprises an antibody against pro-N-cadherin (PNC). Thus, claim 2 is claiming a genus of anti-PNC antibodies for use in the invention. Claim 4 recites an assay using a microarray chip having one or more nucleic acids molecules that can hybridize with a nucleic acid molecule encoding fibroblasts expression PNC or having peptides or antibodies that can bind to fibroblasts expressing PNC. Thus, claim 4 is claiming a genus of any nucleic acids that can hybridize PNC expressing fibroblasts as well as a genus of peptides and a genus of antibodies that can bind PNC expressing fibroblasts. Claim 6 recites administering an anti-fibrotic therapeutic agent capable of inhibiting expression or activity related to PNC expression or activity. Thus, claim 6 recites a genus of therapeutic agents. Claim 7 recites wherein the anti-fibrotic therapeutic agent is a small molecule, a polypeptide or fragment, an siRNA or an antibody or fragment. Thus, claim 7 recites a genus of small molecules, a genus of polypeptides, a genus of siRNAs and a genus of antibodies, all of which are capable of inhibiting expression or activity of PNC. Claim 8 further limits the therapeutic agent of claim 7 to an antibody; thus claim 8 recites a genus of antibodies which inhibit PNC.
In support of the claimed genus(es), the specifications describe only antibodies. This includes the 22 variants of Figure 1, and the anti-PNC antibodies 10A10 and HC5LC4; only the 10A10 and HC5LC4 were reduced to practice. The monoclonal anti-PNC antibody 10A10 (pg. 58; para. 1) was described for detection, and the humanized anti-PNC antibody HC5LC4 was described for blocking activity as a therapeutic antibody (pg. 67, para. 2). The specifications also describe the humanization of 10A10, whereby the CDRs of murine 10A10 were cloned onto human IgG4 heavy and light chain constant domains, resulting in 22 humanized antibodies of Figure 1 (pg. 62, para. 2). Other than describing that HC5LC4 was generated based on IgG4 constant domains, the specifications do not provide the structure of any antibody of the specifications. The only polypeptide amino acid sequence presented in the entire disclosure is that of PNC (pg. 29, para. 1, SEQ ID NO: 1), which is the target antigen. Further, the specifications do not describe a single embodiment of a PNC hybridizing nucleic acid, only how to run ISH and FISH assays, whereby the appropriate probe is used (pg. 43, para. 3). Similarly, the specifications describe concepts of microarrays (pg. 35, para. 3), whereby probes are designed by commercially available designs (pg. 36, para. 5); how to make antibodies (pg. 39); how t use aptamers, or nucleic acid ligands (pg. 44); or oligonucleotides, particularly RNA (pg. 45), including miRNA, siRNA or shRNA (pg. 46); or peptide vaccines (pg. 11 and 28). There are no examples or embodiments of any of these agents that were described, whereby they were specific for PNC; no structures are described, no embodiments were reduced to practice.
Regarding the state of the art of antibodies; it is known in the art that the antigen binding domain of an antibody requires the 6 complementarity determining regions (CDR) of the heavy and light chains, whereby the 3 CDRs of the heavy chain and the 3 CDRs of the light chain are structurally inter-dependent in forming the unique binding pocket of the antibody paratope region; and thus the CDRs constitute critical aspects of the antibody paratope and ultimately impart the paratope-epitope binding functionality with regard to specificity and affinity (for review see MacCallum et al., 1996). However, the structure-to-function correlation continues to be highly unpredictable. For example, Chen et al., (1992) teaches that a single amino acid substitution in the VH CDR2 of PC-specific T15 antibody could increase, decrease or ablate binding the target antigen (abstract, Fig. 3), and this occurred in an unpredictable manner based on which residue was mutated. Similarly, a single point mutation in the heavy chain CDR3 region of the high affinity anti-VEGF antibody G6.31, could in some cases enhance, or otherwise completely ablate binding to the target antigen, and this also occurred in an unpredictable manner (Koenig et al., PNAS, 2017). That is, only screening each mutation individually provided insight as to the resulting changes in functionality. In some cases this extends even beyond the CDRs. Within the framework regions, Koenig et al. (PNAS, 2017) teaches that various amino acid point mutations can increase or decrease binding or neutralization capacity. Some amino acid residues are more tolerant to substitution, while other “conserved” residues are less tolerant, such that a single amino acid substitution may defunctionalize the antibody (pg. E487, Fig. 1). Thus, while antibodies share certain characteristics such as Fc regions or hinge regions, these regions are not correlated with the binding function of the antibody. Conversely, the hyper-variable regions, comprising the complementary set of 6 CDRs, are well established in the art as the portion of the binding regions which impart the specificity of the antibody; and yet, there is no way to look at an amino acid sequence and envision, a priori, whether the combination of six CDRs will bind a particular epitope, even when the CDRs are highly related, without teachings of the basic shared amino acid residues that are sufficient to impart functional binding across all variants. Further, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (pg. 7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on pg. 11). Thus, when claiming a genus of antibodies based on their binding to a common target, the representative examples must cover the full scope of structural variabilities which encompass all species variants that would bind the target.
Section 2163(II)(A)(3)(a)(ii) of the MPEP states that the written description for a claimed genus may be satisfied through either a) a representative number of species, or b) disclosed correlation between function and structure. Here the applicants only reduce to practice 2 antibodies, 10A10 and HC5LC4, which demonstrated binding to PNC such that they may be used in detecting and/or therapeutics against PNC. The applicants do not disclose any structure of any embodiment; therefore no correlation between function and structure can be obtained. This is also true for nucleic acids, for use in microarray chips, or for use in ISH or FISH, small molecules, polypeptides (or peptide vaccines), or siRNAs. No embodiments of any of these agents, wherein the agent is specific for PNC, is described; no structure is provided. Thus, the applicants do not provide any variants of the claimed embodiments, which were reduced to practice; nor do they identify the shared structural properties of the variant antibodies, such as the CDR residues or humanized framework regions, that would define the genus beyond the desired functionality. Currently the essential property of binding PNC is imparted by the specific CDRs of antibody 10A10 and the humanized variants of Figure 1, including HC5LC4; yet even the sequences of the CDRs of 10A10 are not disclosed, nor are the framework region sequences disclosed of any of the humanized variants. Thus, only 2 antibodies, each with unidentified CDR sequences, have been reduced to practice; and that accounts for only the ”antibody” species of the various agents recited in, for example, claim 7. Specifically, the physical features (or amino acid residues encoding said features) which impart the property of binding for detecting or inhibiting for therapeutic value, the target epitope of PNC, should be disclosed. This lack of definition complicates the determination of the boundaries of the claimed genus(es) with regard to which, as of yet unidentified, species variants would be anticipated, a priori, by one skilled in the art, to fall within the scope of the claims.
“The purpose of the written description requirement is to ‘ensure that the scope of the
right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s
contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli
Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D.
Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description
requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed
invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir.
1991). See also MPEP 2163.04. Otherwise, the “claims merely recite a description of the
problem to be solved while claiming all solutions to it and … cover any compound later actually
invented and determined to fall within the claim’s functional boundaries- leaving it to the
pharmaceutical industry to complete an unfinished invention.” Ariad Pharmaceuticals, Inc. v. Eli
Lilly and Co., 598 F.3d 1336, 1353 (Fed. Cir. 2010).
Applicants have not described the genus of antibodies, nor described even a single embodiment of a nucleic acid probe, a small molecule compound, a peptide vaccine, or siRNA which would function in the claimed methods, by binding or inhibiting PNC. Instead applicants seem to contemplate numerous, structurally distinct, agents, with the desired properties of binding or inhibiting PNC, without putting forth the labor of inventing any of them, beyond 10A10 and HC5LC4 antibodies. Even the two antibodies reduced to practice are not described structurally, such that an artisan could appraise the structures for what shared structural feature imparts the inventive concept of being an anti-PNC agent for use in detection and therapy for fibrotic disorders. In view of this uncertainty and the lack of a representative number of examples of the claimed genus, the applicants have failed to show they had possession of the claimed genes(es). Thus, claims 2, 4 and 6-8 are rejected for lack of adequate descriptive support demonstrating possession of the claimed invention.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-2 and 4-5 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Claim 1 recites a method of characterizing a sample, the methods comprising: a) assaying for the presence of aberrant PNC cellular localization and/or circulation in blood in a sample obtained from a human subject; and b) characterizing the sample as i) having pathological fibroblast cells or ii) not having pathological fibroblast cells, based on the presence of aberrant PNC cellular localization or PNC circulation in blood. Thus, the claim is drawn to a process; however, part b) of the process, “characterizing the sample,” is directed to a law of nature (MPEP section 2106.04(b)(I). Specifically, the claim describes the natural correlation between biomarkers, such as PNC cellular localization or PNC in blood, and a pathological fibroblast state. Claim 1 part b) is also directed to an abstract idea (MPEP 2106.04(a)); specifically, a mental process, which includes observation, evaluation and judgment (MPEP 2106.04(a)(2)(III). Claim 1 recites assaying for the presence of, and then characterizing the sample; these steps are mental processes that underlie a law of nature describing the natural relationship between biomarkers and pathological fibroblasts. The relationship between biomarkers and risk of disease is an inherent property, whether known or unknown in the art at the time of filing.
The judicial exception is not integrated into a practical application because the data gathering steps required to make the “characterization” do not add a meaningful limitation to the methods, as they are insignificant extra-solution activity, and the claims do not rely on or use these judicial exceptions in a further steps (MPEP 2106.04(d)). To “assay” a sample, such as by labeling a sample with an antibody (see claim 2) is a general, art-recognized, biological assay for determining biomarkers, and are necessary data-gathering steps. The steps of “assaying” and “characterizing” are recited at a very high level of generality and seem to encompass all methods of detecting the biomarker. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims do not apply or use the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claims as a whole are more than a drafting effort designed to monopolize the exception (MPEP 2106.04(d)). The courts have identified that merely reciting the words “apply it" or, in this case, “characterize the sample”, with the judicial exception does not integrate a judicial exception into a practical application. The instant claims to not recite any other active steps to the method beyond the data-gathering step of detecting biomarkers in a sample and “characterizing” the sample as having pathological fibroblasts, or not. Thus, claim 1 is directed to a law of nature in combination with an abstract idea, which are judicial exceptions, without significantly more, and therefore do not encompass an inventive concept.
Regarding claims 2 and 4; using a generic anti-PNC antibody in the assay, of claim 2, or using an art-recognized microarray chip having a generic nucleic acid which hybridizes to fibroblasts expressing PNC, of claim 4, are alternative data gathering steps that do not add a meaningful limitation to the method as they are insignificant extra-solutions activity. Specifically, immunoassays and/or antibodies, or assaying for nucleic acid molecules using a microarray chip are well-understood, routine and conventional activities in the life sciences.
Regarding claim 5, correlating the presence of pathological fibroblasts (i.e. biomarkers) to fibrosis or a condition associated with fibrosis is a law of nature in that it sets forth diseases that may be naturally correlated with the presence of a specific biomarker.
Thus, claims 2 and 4-5 are directed to a law of nature in combination with an abstract idea, which are judicial exceptions, without significantly more, and therefore do not encompass an inventive concept. As such, claims 2 and 4-5 are rejected for not being drawn to a new or useful process which would qualify as an invention.
Regarding claim 3, if the antibody HC5LC4 were a novel material, it would amount to more than the judicial exception, as the antibody would be a point of novelty to the method. However, as described in the 112(a) rejection for lack of written description (above), it is unclear what the structure of antibody HC5LC4 is, or whether it is novel over generic anti-PNC antibodies of the art. Claims 6-9 overcome the judicial exception of claim 1 by reciting additional elements that integrate the judicial exception into a practical application. Specifically, the claims recite administering an anti-fibrotic therapeutic agent, and therefore effects a particular treatment for a medical condition (however, this would be a method of treating a condition, and not a method of characterizing a sample).
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2 and 4-10 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Ferrell et al., (from IDS, Cite No. 001; US 11,022,608; issued 6/1/2021; henceforth US '608).
The applied reference has common inventors to the instant application; however, as it was published more than one year before the effective filing date of the instant application, it qualifies a prior art under both 35 U.S.C. 102 (a)(1) and (a)(2).
US ‘608 teaches compositions and methods for detecting and treating pathological fibroblast cells (title). US ‘608 claims a method of characterizing a sample comprising assaying for the presence of fibroblast cells expressing PNC in a sample obtained from a human subject, and characterizing the sample as having pathological fibroblasts if fibroblast cells expressing PNC are detected; wherein the presence of pathological fibroblasts indicates the subject is experiencing fibrosis, such as pulmonary fibrosis; and administering to the subject an anti-fibrotic agent which is the anti-PNC antibody 10A10 (col. 39, claim 1). US ‘608 also claims wherein the sample is a blood sample (claim 2). US ‘608 claims wherein the assaying comprises use of an anti-PNC antibody and/or use of a microarray chip having one or more nucleic acids molecules that can hybridize to a nucleic acid encoding fibroblasts expressing PNC (claim 3). US ‘608 claims further administering an additional therapeutic agent, which may be pirfenidone (claim 4).
Regarding claims 1-2 and 4-10; US ‘608 anticipates the method of detecting PNC circulation in a blood sample and characterizing the sample as having pathological fibroblast cells of instant claim 1. US ‘608 anticipates wherein the assay uses an antibody or a microarray chip of instant claims 2 and 4. US ‘608 anticipates wherein the subject is experiencing fibrosis, specifically pulmonary fibrosis, of instant claim 5. US ‘608 anticipates the method further comprising administering an anti-fibrotic agent, which may be the anti-PNC antibody 10A10, of instant claims 6-9. US ‘608 anticipates administering an additional therapeutic agent, which may be pirfenidone, of instant claim 10.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-2 and 5-9 are rejected under 35 U.S.C. 103 as being unpatentable over Bachelder et al., (US 2019/0271703; published 9/5/2019) and Ferrell et al., (from IDS, Cite No: 002; US 2020/0369779; published 11/26/2020).
Bachelder teaches biomarkers for metastatic cancer and methods of treating (abstract). Bachelder teaches the biomarker is pro-N-cadherin (PNC; pg. 1, para. 0013), and antibodies against PNC (para. 0015). Specifically, Bachelder teaches that PNC is expressed on the surface of melanoma and glioma cells and contributes to their invasive behavior, supporting that cell surface expression of PNC is indicative of aberrant cells. Bachelder teaches suitable PNC antibodies are antibodies that specifically bind to pro-N-cadherin, such that they bind the N-terminal pro-N-cadherin region of N-cadherin that is cleaved to form N-cadherin (pg. 7, para. 0085). Bachelder teaches that pro-N-cadherin is specifically found on chemo-resistant tumor cells and that PNC-specific antibodies allow for specific targeting and killing of tumor cells in contrast to an antibody that binds the mature form of N-cadherin, which is found on other normal cell types. Thus, the anti-PNC antibody can be used to detect PNC as a biomarker of cancer cells (pg. 8, para. 0103), and can be used kill chemo-resistant tumor cells which express the PNC biomarker, as a therapeutic (pg. 9, para. 0128). Bachelder teaches numerous assays for detecting PNC, including immunohistochemistry (pg. 9, para. 0112-0125). Bachelder teaches one suitable anti-PNC antibody is mAb 10A10, which can be used to detect aberrant invasive cancer cells (pg. 2, para. 0033; Fig. 4C), or can be used to reduce the number of prostate cancer cells, in vitro (pg. 3, para. 0045; Fig. 9B).
Thus, Bachelder claims a method of diagnosing chemo-residual tumor cells comprising quantifying a biomarker in a sample (pg. 18, claims 1-2), wherein the method further comprises administering anti-cancer therapy (claim 3), wherein the biomarker is PNC (claim 7), wherein the tissue sample is a biological sample of human tissue (claim 12), from cells or blood (claim 13); and wherein the anti-cancer therapy is an anti-PNC antibody (claims 16 and 18-20).
Thus, Bachelder claims a method of detecting aberrant cells via their expression of PNC and a method of treating conditions associated with the aberrant cells, whereby, in both detecting and treating, and anti-PNC antibody is used, and whereby the anti-PNC antibody may be 10A10 antibody.
However, Bachelder does not teach wherein the condition associated with aberrant cells expressing PNC is fibrosis, or comprising fibroblast cells.
Ferrell teaches humanized monoclonal antibodies targeting PNC (title). Ferrell teaches a pathologically mislocated form of N-cadherin is expressed extra-cellularly, and these cells are found in fibrotic conditions of heart, lung, liver and kidney; and that the antibody detects and eliminates the aberrant cells but does not affect cell with normal subcellular location of the protein (abstract). Specifically, Ferrell teaches “cell-surface located PNC serves as a specific target on a subpopulation of myofibroblasts that only exists in pathological settings; thus the specific target can distinguish a pathological fibroblast population from surrounding fibroblasts,” (pg. 2, para. 0020). Ferrell teaches the antibody specifically binds to the pro-domain of pro-N-cadherin (pg. 1, para. 0004); and can serve as a disease-specific diagnostic marker and as a specific therapeutic target for fibrosis (pg. 2, para. 0021). Ferrell teaches suitable antibodies are 10A10 and 19D8, as well as variant humanized heavy and light chains of 10A10 and 19D8 in different combinations (pg. 4, para. 0030; see Table of Sequences, pg. 5). Ferrell demonstrates antibody 10A10 is cytotoxic to PNC-expressing fibroblasts isolated from idiopathic pulmonary fibrosis (pg. 2, para. 0017; Fig. 9).
Thus, Ferrell teaches that PNC expression on the cell surface is indicative of pathological fibroblasts, and that anti-PNC antibody 10A10 may be used to detect and kill pathological fibroblasts isolated from fibrosis tissue.
It would have been obvious to apply the methods of detecting and treating pathological cancer cells expressing cell surface PNC, of Bachelder, to also detect and treat pathological fibroblast cells. One would have been motivated to do so in order to derive a therapeutic strategy for treating fibrosis, as taught by Ferrell. There would have been a reasonable expectation for success given that the anti-PNC antibody 10A10 is taught to detect and kill both cancer cells and pathological fibroblasts, as taught by Bachelder and Ferrell. Thus, the invention was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Regarding claims 1-2; the combination methods of Bachelder and Ferrell make obvious methods of detecting and treating pathological fibroblasts with an anti-PNC antibody (i.e. 10A10), as described above. Bachelder teaches assays, such as IHC (pg. 9,para. 0115), and methods of detecting a biomarker (i.e. PNC) in a tissue sample to distinguish cells expressing the biomarker from cells that do not (pg. 18, claim 5), wherein the biomarker is pro-N-cadherin (claim 7), and wherein the tissue sample is human blood (claims 12-13). Bachelder also teaches wherein the probe used in the methods of detection is an anti-PNC antibody (pg. 8, para. 0110). Thus, the combination of Bachelder and Ferrell makes obvious the methods of detection and diagnosis, using an anti-PNC antibody in an assay, of instant claims 1-2.
Regarding claim 5; Ferrell teaches the detection of pathological fibroblasts of LL97A cells, and that the pathological fibroblasts are indicative of fibrosis, such as pulmonary fibrosis (pg 1, para. 0012; Fig. 2). Thus, the combination of Bachelder and Ferrell make obvious instant claim 5.
Regarding claims 6-9; Bachelder teaches methods of treating comprising administering a therapeutic agent, which is an anti-PNC antibody, which may be antibody 10A10; Ferrell teaches antibody 10A10 kills pathological pulmonary fibroblasts. Thus, the combination of Bachelder and Ferrell makes obvious instant claims 6-8, and wherein the antibody is 10A10, of instant claim 9.
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).
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Claims 1-2 and 4-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 11,022,608; issued 6/1/2021. Although the claims at issue are not identical, they are not patentably distinct from each other because the scope of the claims of US ‘608 anticipates that of the instant claims.
US ‘608 claims a method of characterizing a sample comprising assaying for the presence of fibroblast cells expressing PNC in a sample obtained from a human subject, and characterizing the sample as having pathological fibroblasts if fibroblast cells expressing PNC are detected; wherein the presence of pathological fibroblasts indicates the subject is experiencing fibrosis, such as pulmonary fibrosis; and administering to the subject an anti-fibrotic agent which is the anti-PNC antibody 10A10 (claim 1). US ‘608 also claims wherein the sample is a blood sample (claim 2). US ‘608 claims wherein the assaying comprises use of an anti-PNC antibody and/or use of a microarray chip having one or more nucleic acids molecules that can hybridize to a nucleic acid encoding fibroblasts expressing PNC (claim 3). US ‘608 claims further administering an additional therapeutic agent, which may be pirfenidone (claim 4).
Regarding claims 1-2 and 4-10; US ‘608 anticipates the method of detecting PNC circulation in a blood sample and characterizing the sample as having pathological fibroblast cells of instant claim 1. US ‘608 anticipates wherein the assay uses an antibody or a microarray chip of instant claims 2 and 4. US ‘608 anticipates wherein the subject is experiencing fibrosis, specifically pulmonary fibrosis, of instant claim 5. US ‘608 anticipates the method further comprising administering an anti-fibrotic agent, which may be the anti-PNC antibody 10A10, of instant claims 6-9. US ‘608 anticipates administering an additional therapeutic agent, which may be pirfenidone, of instant claim 10.
Claims 1-2 and 5-9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 5-7 of U.S. Patent No. 11,230,606; issued 1/25/2022 in view of Bachelder et al., (US 2019/0271703; published 9/5/2019).
US ‘606 claims a humanized anti-PNC antibody which binds the pro-domain of PNC, comprising the CDRs of SEQ ID NOs: 22-27 (claim 1), and whereby the antibody is an IgG1 isotype (claim 2). US ‘606 also claims a method of treating a human with a pathological fibrotic condition comprising administering the anti-PNC antibody (claim 5), wherein the fibrotic condition is a disease of the heart, lung, skin, kidney or liver (claim 6), wherein the fibrotic condition is pulmonary fibrosis (claim 7).
Looking to the specifications for clarification of the antibody sequences, the specifications state “variant humanized heavy and light chains of “10A10” are shown in SEQ ID NOs: 35-39; these retain the CDR sequences of the parent murine antibodies,” (col. 6, lines 63-66). The Table of Sequences (cols. 9-10) lists SEQ ID NOs: 35-39 as “clone A10A”, and the CDRs of “clone A10A” are SEQ ID NOs: 22-27. Thus, the examiner asserts that the CDRs of SEQ ID NOs: 22-27, of claim 1, are the CDRs of the “10A10” murine anti-PNC antibody.
Bachelder teaches biomarkers for metastatic cancer and methods of treating (abstract). Bachelder teaches the biomarker is pro-N-cadherin (PNC; pg. 1, para. 0013), and antibodies against PNC (para. 0015). Specifically, Bachelder teaches that PNC is expressed on the surface of melanoma and glioma cells and contributes to their invasive behavior, supporting that cell surface expression of PNC is indicative of aberrant cells. Bachelder teaches suitable PNC antibodies are antibodies that specifically bind to pro-N-cadherin, such that they bind the N-terminal pro-N-cadherin region of N-cadherin that is cleaved to form N-cadherin (pg. 7, para. 0085). Bachelder teaches that pro-N-cadherin is specifically found on chemo-resistant tumor cells and that PNC-specific antibodies allow for specific targeting and killing of tumor cells in contrast to an antibody that binds the mature form of N-cadherin, which is found on other normal cell types. Thus, the anti-PNC antibody can be used to detect PNC as a biomarker of cancer cells (pg. 8, para. 0103), and can be used kill chemo-resistant tumor cells which express the PNC biomarker, as a therapeutic (pg. 9, para. 0128). Bachelder teaches numerous assays for detecting PNC, including immunohistochemistry (pg. 9, para. 0112-0125). Bachelder teaches one suitable anti-PNC antibody is mAb 10A10, which can be used to detect aberrant invasive cancer cells (pg. 2, para. 0033; Fig. 4C), or can be used to reduce the number of prostate cancer cells, in vitro (pg. 3, para. 0045; Fig. 9B).
Thus, Bachelder claims a method of diagnosing chemo-residual tumor cells comprising quantifying a biomarker in a sample (pg. 18, claims 1-2), wherein the method further comprises administering anti-cancer therapy (claim 3), wherein the biomarker is PNC (claim 7), wherein the tissue sample is a biological sample of human tissue (claim 12), from cells or blood (claim 13); and wherein the anti-cancer therapy is an anti-PNC antibody (claims 16 and 18-20).
It would have been obvious to modify the methods of treating fibrosis comprising administering an anti-PNC antibody, of US ‘606, to include methods for detecting and characterizing a sample based on aberrant PNC circulation in the blood, as taught by Bachelder. One would have been motivated to do so in order to improve diagnosing and monitoring progression of a fibrosis-associated condition. There would have been a reasonable expectation for success given that an anti-PNC antibody, which specifically binds to the pro-domain of PNC, which is aberrantly expressed in pathological cells, may be used both for detection of pathological cells and as a therapeutic agent against those same cells, as taught by Bachelder. Further, the anti-PNC antibody of the methods of treating fibrosis, of US ‘606, comprises the same CDRs, and thus has binding specificity for the same epitope of PNC as the anti-PNC antibody 10A10, as disclosed in Bachelder. Thus, as the anti-PNC antibody of Bachelder can be used to both detect and treat pathological cancer cells which aberrantly express PNC on the cell surface, and can also be used to treat pathological fibroblasts expressing PNC, as claimed in US ‘606, it is obvious to incorporate the assays for detecting and characterizing PNC-related pathological cancer cells, of Bachelder, for PNC-related pathological fibroblasts and fibrosis related disorders, to arrive at the instant methods.
Regarding claims 1-2; the combination methods of Bachelder and Ferrell make obvious methods of detecting and treating pathological fibroblasts with an anti-PNC antibody (i.e. 10A10), as described above. Bachelder teaches assays, such as IHC (pg. 9,para. 0115), and methods of detecting a biomarker (i.e. PNC) in a tissue sample to distinguish cells expressing the biomarker from cells that do not (pg. 18, claim 5), wherein the biomarker is pro-N-cadherin (pg. 18, claim 7), and wherein the tissue sample is human blood (pg. 18, claims 12-13). Bachelder also teaches wherein the probe used in the methods of detection is an anti-PNC antibody (pg. 8, para. 0110). Thus, the combination of US ‘606 and Bachelder make obvious the methods of detection and diagnosis, using an anti-PNC antibody in an assay, of instant claims 1-2.
Regarding claim 5; US ‘606 claims methods of treating wherein the pathological fibrotic condition is pulmonary fibrosis (claim 7). Thus, the combination of US ‘606 and Bachelder make obvious methods of detecting aberrant PNC-expressing fibroblasts wherein the presence of the pathological fibroblasts indicate the subject has a condition associated with fibrosis, including pulmonary fibrosis. Thus, the combination of US ‘606 and Bachelder make obvious instant claim 5.
Regarding claims 6-9; Bachelder teaches methods of treating comprising administering a therapeutic agent, which is an anti-PNC antibody, which may be antibody 10A10; US ‘606 teaches humanized anti-PNC antibodies, comprising the identical CDRs of antibody 10A10, kills pathological pulmonary fibroblasts. Thus, the combination of Bachelder and Ferrell makes obvious administering anti-PNC antibody 10A10 as an anti-fibrotic therapeutic agent of instant claims 6-8, and wherein the antibody is 10A10, of instant claim 9.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES R. MELCHIOR whose telephone number is (703)756-4761. The examiner can normally be reached M-F 8:00-5:00 CST.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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