Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1 and 2 are pending and under examination.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1 and 2 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.
“[T]he 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.
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding, binding to a certain epitope), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
Along these same lines, as more recent Federal Circuit decision, Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), describes how when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself not just a description of the sequence to which the antibody binds. Amgen, 872 F.3d at 1378-79.
The importance of this court decision was recently expounded upon by Robert W. Bahr, Deputy Commissioner for Patent Examination Policy in a memorandum clarifying the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) as it relates to claims drawn to antibodies (see Memorandum of February 22, 2018, 2 pages, available at www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf).
Specifically, the so-called “newly characterized antigen” test, which had been based on an example in previously issued USPTO training materials and had been used in the past for determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody is now considered defunct.
The Memorandum explains that USPTO personnel should continue to follow the relevant sections of the MPEP pertaining to the written description requirement of 35 U.S.C. § 112(a) (without regard for any disclosure in the MPEP concerning the use of a fully characterized antigen to provide written description support for an antibody to said antigen).
As described in MPEP § 2163, “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 inventor was in possession of the claimed genus… See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ( "[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he 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.' (internal quotation marks omitted).").
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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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").”
Note well: even if a selection procedure is disclosed that was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad, 94 USPQ2d at 1167; Centocor at 1876 (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
In the instant case, the claims are drawn to “an anti-idiotypic antibody that specifically binds to an IL-23p19 antibody comprising…light chain variable region comprising a…CDRL1…SEQ ID NO: 50, a CDRL2…SEQ ID NO: 56, and a CDRL3…SEQ ID NO: 73…heavy chain variable region comprising a…CDRH1…SEQ ID NO: 5, a CDRH2…SEQ ID NO: 20, and a CDRH3…SEQ ID NO: 44.
According to the instant specification at page 40 last full paragraph:
“Anti-Idiotype Antibodies to Anti-IL-23p19 Antibody Compositions
In addition to monoclonal anti-IL-23p19 antibodies, the present invention is also directed to an anti-idiotypic (anti-Id) antibody specific for such antibodies of the invention. An anti-Id antibody is an antibody which recognizes unique determinants generally associated with the antigen-binding region of another antibody. The anti-Id can be prepared by immunizing an animal of the same species and genetic type (e.g., mouse strain) as the source of the Id antibody with the antibody or a CDR containing region thereof. The immunized animal will recognize and respond to the idiotypic determinants of the immunizing antibody and produce an anti-Id antibody. The anti-Id antibody may also be used as an “immunogen” to induce an immune response in yet another animal, producing a so-called anti-anti-Id antibody.”
However, the instant specification does not teach representative examples of anti-idiotypic (anti-Id) antibodies that bind the antibodies of the instant claims, nor do such anti-Id antibodies seem to be found in the prior art. Moreover, the instant specification does not disclose the particular structural feature(s) critical for the ability of an anti-idiotype antibody to specifically bind the idiotype of the anti-IL-23p19 antibody of the instant claims. Thus, the teachings of the instant specification are insufficient to establish possession of the breadth of the claimed invention consistent with the written description requirement of 35 U.S.C. § 112, 1st paragraph as outlined above.
The number of antibodies having the idiotype binding ability recited in the claims may be vast or it may be small; regardless what is certain is that the number of antibodies that would need to be screened to determine if one has obtained members of the claimed genera representative of their potential diversity is vast.
Note that while an “anti-idiotype” antibody may bind elements integral to the three-dimensional structure of the antibody binding site formed by any one or more of the heavy chain CDR1, CDR2 and/or CDR3 (SEQ ID NOs: 5, 20 and/or 44) and/or the light chain CDR1, CDR2 and/or CDR3 (SEQ ID NOs: 50, 56 and/or 73), yet other “anti-idiotype” may bind variable domain amino acids that occur both within and nearby the CDRs, i.e., in the juxta-CDR framework residues (see, e.g., Carson et al., U.S. Patent No. 5068177 (cited herewith), at col. 2, 6th and 7th full paras).
Note further that several distinct methods were known for generating anti-idiotype antibodies as of the filing date of applicants provisional application, see e.g., Carson at col. 5, 7th para to col. 5-6 bridging para (emphasis added):
“The present invention contemplates synthetic polypeptides that mimic idiotypic antigenic determinants on human rheumatoid factor molecules and elicit the production of antibodies (anti-idiotypic antibodies) of predetermined specificity that are reactive with those idiotypes. Such antibodies can be useful in the treatment of autoimmune disease and certain diseases of B-lymphocytes. Such antibodies can also be used in the diagnosis of disease where a particular idiotype occurs.
An ‘anti-antibody’ or ‘anti-idiotypic antibody’ induced by a peptide of this invention has a predetermined specificity and has a binding site having substantially the same configuration as the primary sequence of the variable or hypervariable region of the immunoglobulin. Antibodies of this type provide an improved means for defining the structure of idiotypes, as well as providing means for diagnostics and therapy.
The method of the present invention produces antibodies against an idiotypic antigenic determinant of a naturally occuring protein and can result, depending on the CDR utilized, in a large fraction of the elicited sera being reactive against the natural and the denatured protein. Specifically, antibodies raised against the second and third CDR of the light chain of IgM-RFs are cross-reactive anti-idiotype antibodies that react with intact and denatured parent protein and the majority of human monoclonal IgM-RFs studied, as described in detail hereinafter. Antisera raised against synthetic peptides corresponding to the third heavy chain CDR consistently recognize idiotypes expressed by intact IgM-RF autoantibodies. In contrast, high titer antibodies against synthetic peptides representing the first and second heavy chain CDR infrequently bind to the intact IgM-RF molecule.”
The teachings of Carson set forth above reflect the knowledge of the ordinarily skilled artisan prior to the date of applicant’s provisional application that only certain CDR regions are useful for generating idiotype-binding, i.e., anti-idiotype antibodies; thus, trial and error experimentation would be required to discern which of any one or more of the heavy chain CDR1, CDR2 and/or CDR3 (SEQ ID NOs: 5, 20 and/or 44) and/or the light chain CDR1, CDR2 and/or CDR3 (SEQ ID NOs: 50, 56 and/or 73) of the instant claims will be effective for generating an anti-idiotypic antibody.
Beyond the peptide modification with keyhole limpet hemocyanin (KLH) and emulsification with complete Freund’s adjuvant (CFA) for various rabbit immunization procedures described by Carson col. 40, at Section VI, parts (A) and (B)(1), the ordinarily skilled artisan further appreciated that anti-idiotype antibodies could also be prepared by ex vivo methods such as phage display (see Suzuki et al., WO2004018521, cited herewith, along with U.S. Patent Application Publication No. 20060247424, which is the English language 371 of the ‘521, also cited herewith, at paras 27-29, 43-44 and Figure 2 of the ‘424).
Thus, even if one were to perform the extensive trial-and-error experimentation to determine which portions of the CDRs of claim 1, or the CDRs + juxta CDR regions of the variable domains of claim 2 could be used to generate anti-idiotype antibodies via a variety of different methods known in the prior art (see the teachings of Carson and Suzuki above), the genus of anti-idiotype antibodies encompassed by the instant claims was of unknowable size / of unknowable sequence space.
To further illustrate the uncertain breadth of the genus of anti-idiotype antibodies encompassed by the instant claims, consider the teachings of Harlow et al. (Antibodies, A Laboratory Manual, Cold Spring Harbor laboratory, 1988, pages 37-47, cited herewith) which describes how the steps of the humoral immune response to an immunogen are dependent on APC, T-cell and B-cell recognition and processing of the immunogen in ways well known in the art to be highly unpredictable and heavily influenced by the particular immunogen and the specifics of the immunization protocol.
The principals laid out in Harlow are further illustrated in the teachings of Edwards et al. (J. Mol. Biol. (2003) 334, 103–118, cited herewith) which shows the immense combinatorial flexibility and capacity of the human antibody repertoire to generate binding sites to an individual protein antigen, the B-lymphocyte growth factor known as “BLyS” (see entire document). Edwards describes in detail how the breadth of antibody structures against a given immunogen can be influenced by the immunization and/or selection methods (see Discussion Section). Moreover, the teachings of Mach 7728114, cited herewith, at Example 1 provide an example of the diversity of immunization protocols.
Like Edwards, Lloyd shows a repertoire of 1x1011 human antibody variable regions can generate large numbers of unique, biologically active scFvs against a variety of polypeptide targets (see Protein Engineering, Design & Selection vol. 22 no. 3 pp. 159–168, 2009, e.g., at page 161-62 bridging paragraph and in Table 1, cited herewith).
As yet another example to illustrate the potential scope of the genus of antibodies encompassed by the instant claims, consider the teachings of Meyer et al. (British Journal of Haematology, 2018, 180, 808–820, cited herewith). Meyer describes the core binding region of the well known anti-CD20 antibody rituximab corresponds to amino acid residues 170ANPS173, wherein N171 is the key residue for binding. By contrast, the OBZ and B1 anti-CD20 antibodies share an overlapping epitope with rituximab (170ANPSEKNSP178); however, by contrast to rituximab, residues at positions 176–178 contribute the most to binding the OBZ and B1 antibodies (see page 809, left col., 2nd full paragraph).
Meyer also described the production and characterization of a panel of new anti-CD20 antibodies which were shown to bind epitopes contained within or nearby the rituximab 170ANPS173 epitope but to bind to different residues than rituximab binds in this region (see page 811, “New CD20 mAbs with overlapping, but distinct epitopes,” see also page 815-16 bridging paragraph).
More particularly, Meyer teaches the newly created anti-CD20 mAbs m1 and m2 were found to bind within but also in the vicinity of the rituximab binding site (m1 and m2) and elsewhere (m2):
“detailed epitope mapping was performed for both mIgG2c-CD20 mAbs m1 and m2, by using PepScan technology. We identified the critical residues of m1 to be 168EPANPSEK175 by using linear (Figure S2A) and circular (Fig 2C, left) peptides with a positional amino acid scan covering the larger extracellular loop. Also for m2, a signal decrease below the WT binding signal occurred within the 168EPANPSEK175 sequence motif but the binding signal to the linear (Figure S2B) and circular (Fig 2C, right) peptide was rather low. This suggests that the epitope of both mAbs is located on the larger loop in the same region, however their binding characteristics are different. The data suggests that m1 binds a linear epitope, whereas m2 binds to a conformational epitope.” (see ibid).
Moreover, while these antibodies bind within or nearby the rituximab 170ANPS173 epitope they do so with heavy and light chain CDRs non-homologous those of rituximab.
Thus, even if multiple antibodies bind epitopes within the same small region of a given polypeptide it is not uncommon for said antibodies to bind to different amino acids even within said small region and for said antibodies to have structurally dissimilar CDRs.
When the above is taken together it is evident that the teachings of the instant specification fail to provide sufficient direction or guidance to put the skilled artisan in possession of the antibodies required to practice the claimed method. Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”). Finally, note that post-effective-filing-date evidence can be relied upon to show that a patent failed to disclose a representative number of species of a claimed genus, see Amgen Inc. v. Sanofi, 872 F.3d 1367, 1375, 124 USPQ2d 1354, 1359 (Fed. Cir. 2017)(MPEP § 2124).
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
