DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claim Status
Claims 1-9 are pending. Claims 1-9 are currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
Title
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
Lengthy Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
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.
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 1-9 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 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus.
The instant claims are drawn to a method of purifying heterodimeric antibodies, the method comprising providing a mixture comprising heterodimeric antibodies and homodimeric antibodies, wherein the heterodimeric antibodies comprise a first human IgG1 heavy chain constant region and a second human IgG1 heavy chain constant region, wherein the first region comprises amino acid modifications L351K and T366K, wherein the numbering is according to the EU index, wherein the first human IgG1 constant region and the second human IgG1 constant region have at least 95% sequence identity to SEQ ID NO:2, wherein the homodimeric antibodies comprise a first homodimeric antibody comprising two of the first human IgG1 heavy chain constant regions and a second homodimeric antibody comprising two of the second human IgG1 heavy chain constant regions and separating the heterodimeric antibodies from the first and second homodimeric antibodies based on a difference in an isoelectric point between the heterodimeric antibodies and the homodimeric antibodies.
The method must purify the antibody, but does not provide the specific steps that are required to produce said purified antibody. The only guidance given by the claims is to separate heterodimeric antibodies from the homodimeric antibodies based on a difference in isolectric point. There is no identification of the steps that would accomplish this function. Dependent claim 9 recites the use of an ion exchange chromatography, but does not provide the type of ion exchange chromatography, or the specific isolation conditions (buffers, pH, etc.) that are necessary to achieve the required purification. Furthermore, the antibodies are not specifically named by sequence, purification of any specific antibody is unpredictable at best.
The claim requires specific purification functions for the method, but the specification provides no guidance regarding which steps (i.e. structures) are capable of the required function. The specification further does not identify a representative number of combinations of antibodies and steps for purification to describe the breadth of the encompassed genus. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
Regarding the encompassed antibodies and fragments thereof, the functional characteristics of antibodies (including binding specificity and affinity) are dictated on their structure. Amino acid sequence and conformation 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. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May;156(9):3285-91 at 3290 and Tables 1 and 2), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
Recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself even when preparation of such an antibody would be routine and conventional. Amgen, 872 F.3d at 1378-79. A key role played by the written description requirement is to prevent “attempt[s] to preempt the future before it has arrived.” Ariad at 1353, (quoting Fiers v. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies. In the instant application, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
The prior art recognizes that the antigen binding by antibodies requires precise orientation of the complementarity determining region (CDR) loops in the variable domain to establish the correct contact surface. For example, Vattekatte, (PeerJ. 2020 Mar 6:8:e8408. doi: 10.7717/peerj.8408. eCollection 2020.) teach that antigen binding in heavy chain only antibodies, (HCAbs) is mediated by only three CDR loops from the single variable domain (VHH) at the N-terminus of each heavy chain, (see abstract). The Vattekatte et al further teach that the amino acid length distribution in different regions of VHH (see Fig. S7) shows diversity in CDR lengths, and that most diversity in CDR3, (see page 7 and 19). However, the prior art also recognizes that a single protein can be bound by a very large and structurally diverse genus of antibodies (i.e., there is no common structural relationship even for antibodies that bind to the same protein, epitope, or overlapping epitopes). For example, Edwards et al. (Mol Biol. 2003 Nov 14;334(1):103-18) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences, and representative of almost the entire extensive heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines), and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well (see table 2, figure 2).
Lloyd et al. (Protein Eng Des Sel. 2009 Mar;22(3):159-68. Epub 2008 Oct 29.) teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding, (abstract). The Lloyd et al reference further teaches that in their studies, of the 841 unselected and 5,044 selected antibodies sequenced, all but one of the 49 functional VH gene segments was observed, and that there are on average about 120 different antibodies generated per antigen (page 167, column 1). Said reference also teaches that a wide variety of VH and VL pairings further increase diversity. (page 159, column 2).
Goel et al. (J Immunol. 2004 Dec 15;173(12):7358-67) teach that three mAbs that bind to the same short (12-mer) peptide, exhibit diverse V gene usage, indicating their independent germline origin. Said reference further teaches that two of these mAbs recognize the same set of amino acid residues defining the epitope (alternate amino acid residues spread over the entire sequence), however, the relative contribution of each set of residues in the peptide showed significant variation. The reference notes that all of the mAbs do not show any kind of V gene restriction among themselves, implying variable paratope structure, despite that two of these mAbs bind to the peptide through a common set of residues. (See entire reference).
Khan et al. (J Immunol (2014) 192 (11): 5398–5405) teach that two structurally diverse germline mAbs recognizing overlapping epitopes of the same short peptide do so in different topologies, the antibodies possessing entirely different CDR sequences. Said reference teaches that unrelated mAbs structurally adjust to recognize an antigen, indicating that the primary B cell response is composed of BCRs having a high degree of structural adaptability. Said reference also teaches that the common epitope(s) also adopt distinct conformations when bound to different mAbs, with the higher degree of structural plasticity inherent to the mAbs. Said reference further teaches “It has been shown that both the framework region and the CDRs have a considerable amount of inherent conformational plasticity...Therefore, it is not surprising that distinct germline Abs recognize the same epitope by rearranging the CDR conformations. This may well have implications of Ag specificity beyond the naive BCR repertoire, because Kaji et al... .have shown in a recent report that the B cell memory can contain both germline-encoded and somatically mutated BCRs.” (See entire reference).
Poosarla et al. (Biotechnol Bioeng. 2017 June ; 114(6): 1331–1342) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Rabia, et al. (Biochem Eng J. 2018 Sep 15:137:365-374. Epub 2018 Jun 5) teach what effects mutations can have on an antibody's stability, solubility, binding affinity and binding specificity. Rabia et al. report that an increase in antibody affinity can be associated with a decrease in stability (p. 366, col. 2 last paragraph; Fig. 2). Rabia et al. thus teach that affinity and specificity are not necessarily correlated and that an increase in affinity does not indicate an increase in specificity (Fig. 3; p. 368, col. 1, section 3,1st full paragraph to col. 2, 2nd full paragraph).
The effects of sequence dissimilarities upon protein structure and function on purification of the protein cannot be predicted and are particularly relevant to determining a functional method for purifying each protein. As taught in Lodish et al (Lodish H, Berk A, Zipursky SL, et al.
New York: W. H. Freeman; 2000), proteins vary in size, charge, and water solubility, and no single method can be used to isolate all proteins (see section 3.5). While any molecule can be separated from a large portion of the other molecules in a lysate based on large differences in some physical characteristics, isolating one particular protein can be a daunting task that requires unique methods for separating the proteins. This is especially true when performing a method that does not make use of immunoaffinity based purifications that can allow for detection of a single, specific protein, as found in the instant method. As taught by Graslund et al (Nat Methods. 2008 February ; 5(2): 135–146), there are difficult strategic choices inherent to the protein purification process. Graslund et al teach that unfortunately, because every protein is different, there can be no 'right' answer to picking a particular strategy a priori, and purification protocols must be worked out for each individual protein with an eye to its intended use (see page 2). Pitfalls that may occur in any purification strategy include additional proteins or multiple protein species or states, which is particular troublesome when the samples contain proteins with different post-translational modifications (see page 12). Additionally, the "pure" samples may precipitate or fail to concentrate, which can also be coupled with sample inhomogeneity. In this case, again, conditions for purification of each individual protein must be worked out, concerning changes of buffer, concentration or adding additional excipients for stability (see page 12).
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: …To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Statement Regarding Prior Art
The closest available prior art is as follows:
Stavenhagen et al (US 2008/0138349 A1; filed 12/7/07; published 6/12/08) teaches purification of molecules that are heterodimers of Fc regions, which comprises Fc regions referring to molecules where the two Fc chains have the same or different sequences (see e.g. paragraph [0046] and [0401]). Exemplary antibody variants include variants containing a N276K mutation (see e.g. Table 2B, particularly page 24) Stavenhagen teaches that the heterodimers can comprise variant Fc regions that have one or more different modifications from the other chain, or one chain can comprise a wild-type Fc region, while the other comprises one or more modifications (see e.g. paragraph [0046]). However, Stavenhagen does not teach the method of the instant claims, including the specific substitutions required for the instant variant Fc region, and therefore does not read on the instant claimed invention.
Lazar et al (US 2011/0054151 A1; filed 9/2/10; published 3/3/11) teaches purification of immunoglobulin compositions that simultaneously co-engage antigens, which preferably utilize heterodimeric Fc regions (see e.g. abstract and paragraph [0053]). The reference describes a heterodimeric protein comprising a L351K/T366K scFv-Fc (see e.g. Figure 6, sheet 8 of 36). However the reference is not prior art under pre-AIA 35 USC 102(b) because the reference publication or issue date of the reference is not more than 1 year prior to the effective filing date of the claimed invention. The reference is not prior art under pre-AIA 35 USC 102(a) and pre-AIA 35 USC 102(e) because the inventive entity of the instant application is not different from that of the reference. Therefore the reference is not applied as prior art.
Behrens et al (WO 2010/106180 A2; filed 3/19/10; published 9/23/10; provided in previous Office Action mailed 5/30/24) teaches purification of variants of polypeptide comprising an Fc region, which exhibits increased binding to FcRn as compared to the parent polypeptide, and comprises at least one amino acid modification in the Fc region (see e.g. abstract and page 74-45, Example 2 ). The variant can comprise a least one amino acid mutation which can comprise 434S, and at least one amino acid modification that can be P228R (see e.g. claim 1). The mutations are according to the numbering of the EU index (see e.g. claim 1). The variant can further comprise a mutation of 428L (see e.g. claim 3). The polypeptide can be a full-length antibody that can be composed of two identical pairs of polypeptide chains, indicating that the two polypeptide chains can both be variants as compared to the wild type parent antibodies, which meets the limitations of instant claim 34 (see e.g. Behrens, page 35, lines 16-28). The antibody can be a fully human antibody (see e.g. page 37, lines 28-37). The antibody can comprise a CH1 at positions 118-220, hinge region at positions 221-236, a CH2 region on positions 237-340, and a CH3 domain at positions 341-447 (see e.g. page 11, line 28-page 12, line 2). However, Behrens does not teach purification of an antibody with the specific substitutions required for the instant variant Fc region, and therefore does not read on the instant claimed invention.
Conclusion
No claim is allowed.
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/ANDREA K MCCOLLUM/ Examiner, Art Unit 1674