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 Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 40-43, 47-49, and 53-59 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 claimed rapid assay to detect human cellular fibronectin (cFn) requires the use of an antibody identified as P1H11 (elected species) having specific functional properties, namely binding an epitope within the EDA domain of cFn (i.e. the amino acid sequence of SEQ ID NO: 4, elected species). However, the properties attributed to the P1H11 clone in the claims are inconsistent and unsupported by the properties of P1H11 clone described in the prior art [Of note, the amino acid sequence of SEQ ID NO: 4 is present in the EDA domain of cFn (see, e.g. US20060024722A1, in particular, Para. 0456 and Sequence Listing for SEQ ID NO: 4)].
Further, claims 42, 49, and 59 encompass sandwich assay formats that use a labelled antibody. Without limitation, the labeled antibody (detection antibody) can be specific for cellular fibronectin; however, the specification acknowledges the difficulty in obtaining high affinity cFn-specific antibody pairs due to limited epitope availability of the EDA region (see Page 10, 2nd paragraph). As presently written, the claims do not recite any specific structure of a labelled antibody that is specific for cFn suitable for use with the capture antibody P1H11 for detection of cellular fibronectin in a sandwich immunoassay
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by 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 genus (MPEP 2163).
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting at 1171, 25 USPQ2d at 1606). Also see (CAFC 2002). Enzo-Biochem v. Gen-Probe Fiers, 984 F.2d 01-1230.
The specification generally teaches multiple antibody development strategies -including phage display panning and mouse immunization – aimed at generating antibodies that recognize cellular fibronectin (cFn), including the EDA domain. A positive antibody was considered to be one that exhibited strong, positive binding to whole cFn and no binding to pFn. Based on these criteria, several antibody clones were reportedly identified, including P1H11 (see Pages 9-10). Notably, however, no epitope mapping, affinity measurements, or quantitative binding data were provided for the initial screening of cFn-specific monoclonal antibodies. Thus, there is no correlation between the structure of the claimed P1H11 clone, alleged by Applicant to be publicly available, and the recited functional properties.
In fact, the P1H11 clone was known in the art at the time of filling to target the cell-binding domain (CBD) of fibronectin, comprising amino acids 1267-1540 of the fibronectin (Kowalczyńska et al, see “Enzyme-linked immunosorbent assay (ELISA)” section; Lee et al, last paragraph of Introduction and Figure 1). The CBD is distinct from the EDA domain, which is only present in cellular fibronectin, not plasma fibronectin. As such, the preexisting P1H11 clone known in the art and publicly available could not inherently possess the recited functional properties of binding to the EDA domain of cFn and with 100-fold greater affinity than to pFn. Further, the specification does not disclose any modification to the preexisting P1H11 clone to alter its epitope specificity from CBD to EDA and achieve the binding affinity for cFn relative to pFn recited in the claims.
Claims 42, 49, and 59 encompass sandwich assay formats that use a labelled antibody. Without further limitation, the labeled antibody (detection antibody) can be specific for cellular fibronectin; however, the specification acknowledges the difficulty in obtaining high affinity cFn-specific antibody pairs due to limited epitope availability of the EDA region (see Page 10, 2nd paragraph). As presently written, the claims do not recite any specific structure of a labelled antibody that is specific for cFn suitable for use with the capture antibody P1H11 for detection of cellular fibronectin in a sandwich immunoassay; and artisans would not be able to readily predict the structure of a cFn-specific labelled antibody that can be paired with P1H11 absent of further guidance provided in the specification.
Therefore, the claimed P1H11 clone lacks adequate written description because there does not appear to be any correlation between the structure of the claimed P1H11 clone and the function of binding to the amino acid sequence of SEQ ID NO: 4 (present in the EDA domain of cFn) and with 100-fold greater affinity than to pFn. The labelled antibody also lacks adequate written description because the specification does not demonstrate possession of a cFn- specific detection antibody suitable for use in a sandwich assay with the claimed P1H11 capture antibody. Thus, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the antibody identified in the claims as P1H11 having the functional properties recited or the labelled antibodies used in the sandwich assay formats at the time the instant application was filed.
Enablement
Claims 40-43, 47-49, and 53-59 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.
The claims are broadly drawn to a rapid assay that determines in 60 minutes or less the level of human cellular fibronectin (cFn) in a test sample obtained from a human test subject, the steps comprising mixing the test sample with the antibody P1H11 (elected species), wherein the antibody binds to cFn with an affinity at least 100-fold greater than it binds to plasma fibronectin and binds to an amino acid sequence of SEQ ID NO: 4 (elected species). Of note, the amino acid sequence of SEQ ID NO: 4 is present in the EDA domain of cFn (see, e.g. US20060024722A1, in particular, Para. 0456 and Sequence Listing for SEQ ID NO: 4).
The specification generally describes multiple antibody development strategies -including phage display panning and mouse immunization – aimed at generating antibodies that recognize cellular fibronectin (cFn), including the EDA domain. A positive antibody was considered to be one that exhibited strong, positive binding to whole cFn and no binding to pFn. Based on these criteria, several antibody clones were reportedly identified, including P1H11 (see Pages 9-10). Following initial screening, selected antibodies—excluding P1H11— were further evaluated as capture antibodies in combination with rabbit anti-fibronectin detection antibody to identify suitable capture/detection antibody pairs. Overall, P4F6 capture antibody/rabbit anti-Fn detection antibody was identified as the best combination in terms of 1) specificity for cFn with no cross-reactivity with fibronectin, 2) low background, 3) adequate spike and recovery performance, and 3) ability to detect cFn in serum and plasma in the described ranges of 0, 0.10-20.0 mg/mL; 1. The ELISA is described as outperforming an existing commercial Biohit kit in linearity and accuracy after optimization of buffers and conditions (Pages 10-11). Additionally, Example I demonstrates the use of P4F6 in a competitive immunoassay performed on the FastPack® IP system in which sample cellular fibronectin competes with immobilized biotinylated cFn for binding to the antibody. In Example II, three c-Fn monoclonal antibodies were evaluated for the detection of cFn in a sandwich-like immunoassay performed on the FastPack® IP system. The cFn monoclonal Abs tested were not specifically identified; however, it is stated that “[a]ll antibodies provided by Prediction BioSciences were biotinylated and enzyme conjugated”. Of note, while initial screening experiments showed that all of the monoclonal Abs paired with rabbit antibody; ‘none of the mono mono pairs gave sufficient signal for use in the evaluation”; therefore, the viability study was based on the use of the mAb P4F6 biotin with rabbit IgG-ALP. The viability of the chemiluminescent immunoassay for cFn on the FastPack® system was demonstrated with a total incubation time of approximately 11 minutes (Pages 19-20).
There is no evidence provided in the specification that the P1H11 clone possess the claimed functional properties of binding the EDA domain of cellular fibronectin (specifically amino acid sequence of SEQ ID NO: 4) and with 100-fold greater affinity than to plasma fibronectin. Notably,
no epitope mapping, affinity measurements, or quantitative binding data were provided for the initial screening of cFn-specific monoclonal antibodies.
To the contrary, the P1H11 clone was known in the art at the time of filling to target the cell-binding domain (CBD) of fibronectin, comprising amino acids 1267-1540 of fibronectin (Kowalczyńska et al, see “Enzyme-linked immunosorbent assay (ELISA)” section; Lee et al, last paragraph of Introduction and Figure 1). The CBD region is distinct from the EDA domain which is only present in cellular fibronectin, not plasma fibronectin (see Page 11, 2nd paragraph of Specification). Without further evidence, artisans would not reasonably expect the preexisting P1H11 clone to bind the EDA domain of cFn (specifically the amino acid sequence of SEQ ID NO: 4) and with 100-fold greater affinity than to pFn.
Further, the specification explicitly acknowledges several limitations in the generation of antibodies specific for cFn including 1) limited epitope availability: the EDA region unique to cFn is not a prevalent antibody-binding site; 2) inability to form high affinity Ab pairs: the limited binding region prevents generation of two high-affinity, cFn-specific antibodies for sandwich ELISAs; and 3) antigen instability: cFn rapidly degrades and/or loses EDA antigenicity, including during freeze-thaw cycles (Page 11, 2nd and 3rd paragraphs). These limitations further underscore the unpredictability of obtaining antibodies specific for cFn with the claimed specificity.
Claims 42, 49, and 59 encompass sandwich assay formats that use a labelled antibody. Without further limitation, the labeled antibody (detection antibody) can be specific for cellular fibronectin; however, as stated above, there is difficulty in obtaining high affinity cFn-specific antibody pairs due to limited epitope availability of the EDA region (see Page 10, 2nd paragraph). Thus, artisans would not reasonably expect that any cFn-specific labelled antibody would be suitable for use with P1H11 as the capture antibody to effectively detect cellular fibronectin in a sandwich immunoassay absent of evidence provided to the contrary.
Since pFn is present in blood, serum, and plasma at concentrations approximately 100-fold greater than cFn (see Page 11 of Specification), the P1H11 clone would predominantly bind plasma fibronectin in a biological sample and thus cannot be used for the detection of cFn, specifically absent of evidence to the contrary. While figure 10 demonstrates that a chemiluminescent signal may be obtained in a FastPack® sandwich assay format within a short incubation time using biotinylated P1H11 in combination with rabbit anti-fibronectin conjugate, this experiment does not demonstrate preferential binding to cFn relative to plasma fibronectin and does not establish that the measured signal corresponds specifically to cFn rather than to the substantially more abundant plasma fibronectin.
Lastly, inconsistencies between the properties of the antibody clone identified as “P1H11” in the prior art and the properties attributed to “P1H11” in the present claims raise a question as to whether the antibody required to practice the claimed invention was, in fact, publicly available. In response to Applicant submitted an affidavit on 12/16/2020 asserting that P1H11 was commercially available as of the priority date for this application (April 13, 2012) and provides packing lists identifying the delivery of P1H11 prior to April 13, 2012 (see Attachments A and B from Affidavint/Declaration dated 12/16/2020). However, correspondence from the founder and president of Affinity Life Sciences indicates that Affinity worked with Applicant on the development of several cellular fibronectin (cFn) antibodies on a contract service basis and that rights and that an agreement related to their commercialization was not established until June 13, 2012—after the April 13, 2012 priority date. The letter does not state that P1H11 having the claimed properties was publicly available or accessible. Rather, the letter appears to indicate that cFn-specific antibodies were generated specifically for applicant, contradicting the affidavit’s assertion of commercial availability. If the claimed P1H11 antibody is materially different from the P1H11 clone described in the prior art, then the antibody required to practice the claimed invention has not been shown to be publicly available or identifiable based on the disclosure. The claimed P1H11 is a required element of the rapid assay to detect human cellular fibronectin. As such, the claimed P1H11 clone having the recited functional properties must be known and readily available or obtainable by a repeatable method set forth in the specification, or otherwise known and readily available to the public. If it is not so obtainable or available, the requirements of 35 USC 112(a), first paragraph, may be satisfied by a deposit of the biological material.
Further in line with this concern, Applicant has argued that both the standard FastPack® immunoassay and instrument were modified by Qualigen to facilitate removal of plasma fibronectin, yet citing only the inclusion of a wash step to remove plasma fibronectin such that only bound cFn remains (Remarks of 09/23/2025, Page 9, 4th paragraph). This statement suggests that other modifications were made to the FastPack® assay and instrument besides use of a wash step. Indeed, Applicant goes on to assert that they “have already established that they literally had to have the FastPack® IP system by Qualigen, Inc. specifically modified to even allow for the possibility to realize their claimed methods” (Remarks of 09/23/2025, Page 10, 2nd paragraph). However, the specification does not disclose any additional assay or instrument modifications beyond routine wash steps, which are standard in ELISA-type assays, including FastPack® assays (see, e.g. Naselli et al and FastPack® Total PSA immunoassay, of record), and function to remove unbound material (Hamnett, see “Washing” section). If a person of ordinary skill in the art cannot obtain or use the necessary undisclosed or proprietary instrument/assay, they cannot practice the claimed invention without an undue amount of experimentation, especially absence of any further guidance in the specification to replicate said undisclosed modifications to the FastPack® immunoassay and instrumentation.
Therefore, the specification is not enabling over the full scope of the claims.
Response to Arguments
Applicant’s arguments filed 09/23/2025 with respect to the rejection(s) of claims under 35 USC 112(b) and 35 USC 112(d) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. Applicant’s arguments concerning the prior art properties of the P1H11 antibody have been considered. In view of the claim requirement that the P1H11 antibody bind an epitope within the EDA domain of cFn (particularly, the amino acid sequence of SEQ ID NO: 4) and exhibit at least 100-fold greater affinity for cFn relative to plasma fibronectin, the P1H11 clone described in the prior art does not possess the recited functional properties. The specification, however, does not provide experimental data or characterization demonstrating that the antibody identified as P1H11 in the claims has these properties. Accordingly, the rejections made under 35 USC 103 and double patenting are also withdrawn at this time; however, for the reasons discussed above, the claims are rejected under 35 USC 112(a) for lack of written description and enablement.
Further underscoring lack of enablement, Applicant has asserted that the claimed method relies on modifications to the Qualigen FastPack® assay and instrument; however, the specification does not disclose any such modifications beyond routine immunoassay washing steps nor establish that any modified system required to practice the claims was publicly available. The specification also does not otherwise provide guidance to one of ordinary skill in the art on how to replicate any modifications made to both the FastPack® standard assay and instrumentation in order to practice the claimed method.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641
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