Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Status of the claims
Claims 34-35, 41-42, 45-48 and 55-56 are pending and examined on merits.
Claim Rejections Maintained - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 41 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 41 recites “said conjugate” for which the claim does not have a clear antecedent basis. The term “conjugate” has not been recited anywhere in claim 34 from which claim 41 depends. Thus, it is unclear what conjugates are intended in claim 41 by the recitation “said conjugate”.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 34-35, 41-42, 45-48, 55 and 56 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 34-35, 41-42, 45-48 and 55-56 directed to method of detecting gabapentin requiring anti-gabapentin antibody capable of forming complex with gabapentin in a sample and the anti-gabapentin antibody is critical to practice the invention. Claim 56 directed to a kit, which in addition to the anti-gabapentin antibody, also comprises a gabapentin conjugate having the structure
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As claimed, the epitope on the conjugate to which the antibody binds have not been disclosed and thus the genus of the claimed antibody encompass various antibodies directed to various epitopes on the conjugate including epitope on the linker, linker-enzyme conjugation site, linker-hapten conjugation site and various sites on the hapten portion of the conjugates.
However, the only disclosure of antibody specifically binding of Gabapentin in the specification is strictly limited to a polyclonal antibody generated against a specific conjugate of a hapten with an immunogenic carrier (KLH) having the structure
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(structure 51) wherein the specificity of the antibody has been determined with a polyclonal antibody designated with #10930 (paragraphs [00308], [00314] and [00316]). The instant application does not provide adequate written description for all the various antibodies as described above for various epitopes and various antibody fragments, various antibodies directed to various epitopes in gabapentin, and recombinant antibodies yet to be discovered that binds to a specific epitope on the conjugate. Although screening applications are well known in the art to identify antibodies, screening is only a wish or plan for the future invention of undiscovered, unknown antibodies (the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention). Applicants have not described representative species of antibody structures that functions as claimed to adequately describe the entire genus of antibodies for various epitopes on the conjugate to practice the process of detection. From the disclosed polyclonal antibody #10930, one would not readily envision or predict the CDR sequences of any and all other future, undiscovered polyclonal, monoclonal, recombinant and fragment antibodies directed to various epitopes on the conjugate structure. In view of recent Amgen decision, adequate written description of a newly characterized antigen should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.
A definition by function does not suffice to define the genus because it is only an indication of what the antibody does, rather than what it is. A description of a genus of antibodies may be achieved by means of a recitation of a representative number of antibodies, defined by sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. The written description requirement can be met by showing that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics ....i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. The only disclosed polyclonal antibody against a specific conjugate in the specification are not representative of, nor predictive of any and all other antibody sequences for the broadly claimed genus. There is no common/shared structure disclosed among the antibodies having the claimed binding function. The instant claims attempt to claim every antibody that binds to a broad epitope on the gabapentin conjugate. However, the instant specification does not describe sufficient representative structures of antibodies with binding sequences (CDRs) to support the full scope of the claims. Applicants are directed to the recent and relevant decision in AbbVie Deutschland GmbH v. Janssen Biotech, Inc. (Fed. Cir. 2014). The court found that if the disclosed species only abide in a corner of the genus, one has not described the genus sufficiently to show that the inventor invented, or had possession of, the genus. He only described a portion of it. In the instant case, the claims broadly encompass various species of antibodies binding to various epitopes on the gabapentin conjugate, but however the specification disclosed only a polyclonal antibody and the disclosed polyclonal antibody does not predict the CDR sequence/structure of any and all other antibodies yet to be discovered that function as claimed and moreover, polyclonal antibody having the same structure cannot be reliably reproducible by immunizing the same animal with the same immunogenic conjugate. Applicants have not established any reasonable structure-function correlation with regards to the antibody sequences required to bind a single epitope on the gabapentin conjugate let alone the entire genus of antibodies binding to various epitopes on the gabapentin conjugate. The exemplary polyclonal antibody do not provide antibody sequence or sequence homology for the function of binding within claimed recognition. The instant specification does not describe representative examples to support the full scope of the claims because the instant specification discloses only one polyclonal antibody which does not provide specific variable regions and/or CDRs having the desired binding specificity and affinity and does not provide common shared structures for the various species of antibodies binding to various epitopes on the gabapentin conjugate.
Claims are broadly drawn to various antibodies (monoclonal, single chain antibody, antibody fragments, and recombinant) but, however, the instant specification only disclosed a polyclonal antibody binding to gabaapentin, which does not provide any knowledge or prediction of the three CDRs from light chain and the three CDRs from heaving chain required from specific binding to an epitope on the gabapentin conjugate. The instant specification does not provide any disclosure or any binding sequences for any antibody for light chain CDR sequences and heavy chain CDR sequences. A disclosure of a polyclonal antibody cannot be considered representative of a fragment of an antibody, a recombinant antibody or a single chain antibody without having knowing the CDR sequences of an antibody having recognition specificity of a specific epitope, let alone binding sequences for various other epitopes on the gabapentin sequences. It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al (Proc Natl Acad Sci USA 1982 Vol 79 page 1979). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
An adequate written description must contain enough information about the actual makeup of the claimed antibody for detection, "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." The functional requirement that the required claimed antibodies binds to gabapentin conjugate having the structure disclosed in claim 55 is the sort of wish list of properties which fails to satisfy the written description requirement because "antibodies with those properties have not been adequately described." Centocor, 636 F.3d at 1352. The instant specification generated only a polyclonal antibody to gabapentin without disclosing any epitope binding and which also fails to provide common structural features or to provide guidance regarding the full scope of monoclonal antibodies, antibody fragments, single chain antibody and recombinant antibodies. The specification does not adequately describe a representative number of members of the genus or provide a written description of the genus of structurally different antibodies that bind to an epitope on the various epitope structures represented by the formula of claim 55. Since the disclosure fails to describe common attributes or characteristics that adequately identify members of antibodies of the genus, and because the genus is highly variant, the disclosure of generating antibodies and disclosure of a polyclonal antibody that bind to gabapentin is insufficient to describe the entire genus of various antibodies directed to various epitopes on the structure of formula of claim 55. As stated by the Federal Circuit, "[i]n order to demonstrate that [Appellants have] invented what is claimed, [Appellants' Specification] must adequately describe representative antibodies to reflect the structural diversity of the claimed genus." Abbvie, 759 F.3d at 1301. "[F]unctionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date." Id. The record here does not indicate an established structure-function correlation between the claimed antibody utilized for the process and the binding function. Here, in this case, not a single sequence of a monoclonal antibody has been disclosed let alone the structure-function correlation for the various antibodies having binding specificities to various epitope on the gabapentin conjugate. Disclosure of only a polyclonal antibody cannot be representative of the entire genus of antibodies as encompassed by the claims.
Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of antibody species to describe the genus as broadly claimed and therefore, claims 34-35, 41-42, 45-48 and 55-56 are rejected for not adequately providing written description for the entire instantly claimed genus.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 34-35, 41-42, and 45-48 are rejected under 35 U.S.C. 103(a) as being unpatentable over Juenke et al (Clinical Chemistry 2003) in view of Nolli et al (Ann. Ist Super. Sanita 1991; Cite # 20 in the IDS of 3/4/24), Stenman (Clinical Chemistry 2005) and Mayer (Angewandle Chemie 1994; Cite # 16 in the IDS of 3/4/24).
In regards to claims 34, Juenke et al teach Gabapentin as a therapeutic drug mostly used as adjunctive epileptic therapy in addition to other treatments (see page 1198, first paragraph of right column). Juenke et al teach that Gabapentin exhibits saturable absorption, making it a nonlinear drug and kinetically less predictable and dose-response pattern is apparent from plasma gabapentin concentrations and therefore, monitoring of plasma gabapectin is most useful to establish compliance. Juenke et al teach detection of plasma gabapentin using spectrofluorometry, HPLC, mass spectrometry and Gas chromatography.
Juenke et al however, do not teach immunoassay detection of Gabapentin.
Nolli et al teach that immunological detection method beside possessing reasonable sensitivity, accuracy and precision, have the potential of showing a significant degree of specificity since they are based on the recognition of structural components of the molecule. Nolli et al teach that immunological assays can detect all moieties, microbiologically active or not, that have a structure that can evoke the antigenic response. Nolli et al further teach generalized teaching for production of antibodies against small molecule drugs (e.g. antibiotics) for assay of drug concentrations in blood, urine and other body fluids. Nolli et al teach that small molecules can be made immunogenic by conjugation with an immunogenic carrier (see "antibodies against antibiotic section") and teach different immunogenic carriers (see table 2) and potential positions on the hapten (e.g. amino group) for linking the carriers (see table 3). Nolli et al disclose that polyclonal antibodies containing mixed population of antibodies (against different antigenic sites of the hapten) are largely used to set up enzyme immunoassays for antibiotics but however, monoclonal antibodies (i.e. antibodies that recognize one antigenic site of the hapten) have a better specificity for the hapten (see summary and sections under the headings "Need for antibiotics assay", "antibodies against antibiotics" and “monoclonal versus polyclonal antibodies").
Stenman teaches that the specificity of the antigen-antibody reaction is astounding and it is possible to measure picomolar concentrations of proteins, peptides and haptens in the presence of 10 million-fold excess of closely related molecules (page 801, left column, lines 19-22).
Mayer discloses immunoassay detection and quantitation of analytes. Mayer et al teach labeling of specific binding reagents (e.g. antibody) with a non-isotopic label for immunoassay detection of the corresponding binding partner in an sample (see introduction). Throughout the reference, Mayer et al teach various non-isotopic detection label which includes fluorophore, enzyme (e.g. horseradish peroxidase) and chemiluminescent label. Mayer teaches various types of immunoassays (page 1045).
Therefore, as evidenced by Nolli et al, once a drug is established, it is obvious to make corresponding antibody and monoclonal antibody against the drug for high sensitive immunological detection/assay of the drug and since Gabapentin is a well established as a therapeutic drug and its detection in blood is important for establishing optimal effective dose in a patient (Juenke et al) and since immunogenic detection is advantageous for being specific and accurate (Noli et al), it would be obvious to make the corresponding antibody to this drug in accordance with the reasoning set forth in Ex parte Erlich, 3 USPQ2d 1011 (1987), in particular, paragraph [5] of page 1016. It would have been obvious to one of ordinary skill in the art the time of the invention to produce antibody against the Gabapentin drug with the expectation of immunological detection of therapeutic concentration of the drug in serum because Nolli teaches that antibody mediated detection provides specific and accurate detection of a drug in a serum or urine sample and Stenman teaches that antibody mediated detection can measure picomolar concentrations of proteins, peptides and haptens in the presence of 10 million-fold excess of closely related molecules. Reasonable expectation of success in obtaining monoclonal antibody against the Gabapentin comes from Nolli et al’s teaching of the conventional preparation methods of immunogenic carrier to activated drug haptens, immunogens, tracers, and corresponding antibodies using reactive groups on the hapten (e.g. amine group, carboxylic acid group) and since Gabapectin comprises free amino and carboxylic acid groups, one of ordinary skill in the art would consider the functional groups as a potential reactive group for conjugation of the drug to an immunogenic carrier. Further, once a compound has been established as a potential drug for therapeutic application, one of ordinary skill in the art would be motivated to establish a high sensitive assay to monitor the drug concentration in blood, urine and other body fluids and tissues which are essential for studying pharmacology and pharmacokinetics of the drug and to establish therapeutic level of the drug in various body compartments. Moreover, one of ordinary skill in the art, from the teaching of Nolli et al would have been motivated to generate monoclonal antibody against Gabapentin because Nolli et al teach that monoclonal antibodies have better specificity for haptens than polyclonal antibody.
In regards to 35, 42-44, 45-48 and 55, once an antibody is known specific for a drug, one of ordinary skilled in the art from the description in mind of Mayer, can easily envisage various immunoassay including homogeneous, heterogeneous and quantitative detection of the drug in various samples with a reasonable expectation of success. Moreover, Stenman teaches monitoring gabapectin in serum and thus it would be obvious to screen for antibodies that has low cross-reactivity to other molecules present in the serum and various other samples.
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 §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 34-35, 41-42, 45-48, 55 and 56 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-36 of U.S. Patent No.8,828,665. Although the claims at issue are not identical, they are not patentably distinct from each other because the subject matter of instant claims are fully disclosed in the claims of US patent ‘665. Claims of US patent ‘665 discloses antibody specifically binding to gabapentin and gabapentin conjugates wherein the antibody may be polyclonal, monoclonal, and antibody fragments (see claim 1-19). The US patent ‘665 also discloses antibody binding to conjugates having a conjugate wherein the conjugate is of the same structure as claimed in instant claim. Therefore, the subject matter of instant claims are broadly encompassed or are obvious from the claims of the US patent ‘665.
Claims 34-35, 41-42, 45-48, 55 and 56 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No.10203345. Although the claims at issue are not identical, they are not patentably distinct from each other because the subject matter of instant claims are fully disclosed in the claims of US patent ‘345. Claims of US patent ‘345 discloses antibody specifically binding to gabapentin and gabapentin conjugates (see claim 28). The US patent ‘345 also discloses antibody binding to conjugates having a conjugate wherein the conjugate is of the same structure as claimed in instant claim (see claims 1-28). Therefore, the subject matter of instant claims are broadly encompassed or are obvious from the claims of the US patent ‘345.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHAFIQUL HAQ whose telephone number is (571)272-6103. The examiner can normally be reached on Mon-Fri 8-4:30.
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/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678
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