The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
The amendment filed on 10-15-2025 is acknowledged. Claims 1 and 3-5 have been amended. Claims 1-7, 9-15, 17-18, 20 and 22-24 are pending. Claims 7, 11-15, 17, 20 and 22-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-6, 9-10 and 18 are currently under examination.
Claim Rejections Maintained
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.
The rejection of claims 1-5, 9-10 and 18 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. Cancellation of claims 26-28 has rendered the rejection of those claims moot. 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.
Applicant argues:
1. Claim 1 to has been amended to recite "[a] nucleic acid molecule encoding one or more synthetic antibodies, wherein the nucleic acid molecule encodes at least one amino acid sequence selected from the group consisting of a) the amino acid sequence as set forth in SEQ ID NO:2; and b) a functional fragment of the amino acid sequence as set forth in SEQ ID NO:2; or wherein the nucleic acid molecule comprises at least one nucleotide sequence selected from the group consisting of a) the nucleotide sequence as set forth SEQ ID NO: 1; and b) a functional fragment of the nucleotide sequence as set forth in SEQ ID NO: 1; or wherein the nucleic acid molecule comprises a nucleotide sequence encoding a variable heavy chain region and a variable light chain region, wherein the sequence encoding a variable heavy chain region is selected from the group consisting of: a) a nucleotide sequence encoding the amino acid sequence as set forth in SEQ ID NO:4; b) the nucleotide sequence as set forth in SEQ ID NO:3; and wherein the sequence encoding a variable light chain region is selected from the group consisting of: a) a nucleotide sequence encoding the amino acid sequence as set forth in SEQ ID NO:6; b) the nucleotide sequence as set forth in SEQ ID NO:5; and wherein the one or more synthetic antibodies binds to the OspA protein."
2. Claim 3 has been amended to recite "group consisting of a) the amino acid sequence as set forth in SEQ ID NO:2; and b) a functional fragment of the amino acid sequence as set forth SEQ ID NO:2."
3. Claim 4 has been amended to recite "group consisting of a) the nucleotide sequence as set forth in SEQ ID NO: 1; and b) a functional fragment of the nucleotide sequence as set forth in SEQ ID NO:1.".
4. Claim 5 has been amended to recite "group consisting of: a) a nucleotide sequence encoding the amino acid sequence as set forth in SEQ ID NO:4; and b) the nucleotide sequence as set forth in SEQ ID NO:3 and wherein the sequence encoding a variable light chain region is selected from the group consisting of: a) a nucleotide sequence encoding the amino acid sequence as set forth in SEQ ID NO:6; and b) the nucleotide sequence as set forth in SEQ ID NO:5.".
5. The claimed subject matter, as presently amended, is directed to sequences encoding the DMab 319- 44modl antibody, which the Examiner has conceded to fulfill the written description requirement, and functional fragments thereof and that a skilled artisan in observing the successful application of the DMab 319-44modl antibody as documented in the Specification as filed at least in Example 1, will appreciate that functional fragments will share the common characteristic of functionally binding to the OspA antigen. Accordingly, a skilled artisan will appreciate that the Specification as-filed discloses a representative number of species sufficient to demonstrate that the inventors had possession of the claimed subject matter.
6. The instant specification details the specific sequences, i.e., structural chemical formulas, with which the skilled artisan can construct the synthetic OspA antibody (e.g., paragraphs [0007]-[0008], [0019], [0021], [00104]-[00108], [00161], and [00222]); provides direction on how to modify the antibody appropriately (e.g., paragraphs [00181]-[00184]); teaches how to use it to perform the biological function of binding to the OspA protein (e.g., paragraphs [00194] and [00202]); and demonstrates how to evaluate successful production of a synthetic antibody that performs the biological function of binding to or reacting with the OspA protein (e.g., paragraphs [0042], [0043], [00202], [00239], [00240], Figures 6C and 7B, and Example 1).
7. The level of skill and readily available knowledge in the art with respect to antibodies is high. Accordingly, one skilled in the art can readily obtain functional fragments of the claimed antibodies. Further, the ability of such antibodies to bind the OspA protein can be readily assessed through the direction of the instant Specification (See, e.g., Example 1).
8. The written description requirement must be analyzed in context of the knowledge of the skilled artisan, which in this case includes extensive sequence and functional data regarding antibodies, and extensive knowledge regarding production of mutants, variants and homologs of a protein of interest to identify proteins having a desired biological activity, e.g., an antibody that specifically binds to the OspA protein. This is especially true where the specification provides extensive reduction to practice, including, but not limited to, working examples of the claimed antibodies and assays that can be used to identify additional antibodies of the invention (see e.g., Figures 6C and 7B, Example 1).
Applicant’s arguments have been fully considered and deemed non-persuasive.
With regard to Points 1-4, the amendment to the instant claims is insufficient to overcome the rejection as there is still no correlation between structure (sequence) and function (binding of an undefined OspA) as required by the written description requirements.
With regard to Point 5, contrary to Applicant’s assertion, the instant claims are not limited to the DMab 319-44mod1 antibody. While SEQ ID NO:3-4 recite the heavy chain of the DMab 319-44mod1 antibody and SEQ ID NO:5-6 recite the light chain of said antibody, the claims are not limited to antibodies with those sequences. The instant claims encompass antibodies comprising one or more of the recited sequences (or fragments thereof). Consequently While the skilled artisan might be able to envision all variants within the claimed genus, they would not be able to predict which of those variants (if any) would have the ability to bind to a given OspA given that the specification merely refers to variants of the DMab 319-44mod1 antibody in a prophetic sense but is silent with regard to what specific combination of sequences would result in the ability to bind to a given OspA. Therefore, the specification fails to adequately describe at least a substantial number of members of the genus of antibodies (and therefor the nucleic acids encoding them) to which the claims refer.
With regard to Point 6, Applicant is reminded that 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. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, contrary to Applicant’s assertion, the cited references do not disclose the specific sequences that must be present in order for a given synthetic antibody to bind to an OspA protein. Paragraphs [007]-[008] and [0021] prophetically states that the encoded antibody can have up to 95% sequence identity to SEQ ID NO:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24-27 or that said nucleic acid encoding said antibodies can have at least 95% sequence identity to SEQ ID NO:1, 3, 5, 7, 9, 11, 13, 15, 17, 18, 20 or 21 but is silent with regard to what residues within said sequence are required for binding to a given OspA protein. Paragraph [0019] refers to:
“…an amino acid molecule comprising one or more synthetic antibodies, wherein the amino acid molecule comprises at least one selected from the group consisting of an amino acid sequence comprising an anti-OspA synthetic antibody, and an amino acid sequence comprising a fragment of an anti-OspA synthetic antibody.”
But is silent with regard to the specific sequences required for binding to a given OspA protein. Paragraphs [00104]-[00108] and [00161] discuss the generalized structure of the disclosed antibodies (i.e. compose a VH region, at least one CH region; a VL region, at least one CL region. Again the specification is silent with regard to the specific sequences required for binding to a given OspA protein. Finally, as noted by Applicant, the specification clearly discloses that the “variant antibodies” have to be screened for biological activity.
With regard to Points 7 and 8, Applicant’s point was addressed in Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1084 (Fed. Cir. 2005). The crux of the Capon decision is what is known in the art. In the Capon decision, the CAFC stated “In summary, the Board erred in ruling that §112 imposes a per se rule requiring recitation in the specification of the nucleotide of claimed DNA when that sequence is already known in the field. However, the Board did not explore the support for each of the claims of both parties in view of the specific examples and general teachings in the specifications and the known science with application of precedent guiding review of the scope of the claims.” The CAFC determined that the correlation between structure and function, required to meet the written description requirements, were known in the art. This is not the case with regard to the instant claims as the residues within the recited sequences that are required for a given antibody to bind to OspA are not known in the art. Consequently, the Capon decision is not germane to the instant rejection. Moreover, given the unlikelihood of predicting which mutations would not affect antigen binding, the “art” cannot be relied upon for making up for the deficits of the specification.
As outlined previously, the instant claims are drawn to nucleic acids encoding antibodies that bind to an undefined OspA wherein said antibodies comprise one or more sequences based on SEQ ID NO:1-6 (or fragments thereof).
The specification discloses a single antibody DMab 319-44mod1 that binds OspA and contains the recited sequence. This antibody (and hence the nucleic acid encoding it) meets the written description provision of 35 USC 112, first paragraph. However, the aforementioned claims are directed to encompass all antibodies comprising a multiplicity of the sequences of SEQ ID NO:1-6 and fragments thereof. None of these antibodies meet the written description provision of 35 USC 112, first paragraph since the specification is silent as to what combination of sequences (e.g. immunoepitopes and framework regions) are required for a given antibody to bind to a given OspA.
To fulfill the written description requirements set forth under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative member of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicant has possession the claimed invention. To adequately describe the genus of antibodies, Applicant must adequately which combination of the recited sequences (e.g. heavy chain and light chain sequences) give rise to an antibody with the claimed immunological function. The specification, however, does not disclose distinguishing and identifying features of a representative number of members of the genus of antibodies to which the claims are drawn, such as a correlation between the structure of the light and heavy chains and its recited function (antibody binding to OspA), so that the skilled artisan could immediately envision, or recognize at least a substantial number of members of the claimed genus of antibodies. Moreover, the specification fails to disclose what combination of sequences based on SEQ ID NO:1-6 (and fragments thereof) would result in an antibody capable of binding to a given OspA. Therefore, the specification fails to adequately describe at least a substantial number of members of the genus of antibodies to which the claims refer.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow persons 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. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
MPEP 2163.02 further states, “[p]ossession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention” See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997); Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). Moreover, because the claims encompass a genus of variant species, 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 Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Additionally, MPEP 2163 states:
"A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)”
And:
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).
As evidenced by the teachings of Skolnick et al., the art is unpredictable. Skolnick et al. (Trends in Biotechnology 18: 34-39, 2000) discloses the skilled artisan is well aware that assigning functional activities for any particular protein or protein family based upon sequence homology is inaccurate, in part because of the multifunctional nature of proteins (see, e.g., the abstract; and page 34, Sequence-based approaches to function prediction). Even in situations where there is some confidence of a similar overall structure between two proteins, only experimental research can confirm the artisan's best guess as to the function of the structurally related protein (see, in particular, the abstract and Box 2). Thus, one skilled in the art would not accept the assertion, which is based only upon an observed similarity in amino acid sequence that a variant of a given antibody would necessarily bind to a given polypeptide. Moreover, as evidenced by Greenspan et al. (Nature Biotechnology 7: 936-937, 1999), defining epitopes is not as easy as it seems. Greenspan et al. recommends defining an epitope by the structural characterization of the molecular interface between the antigen and the antibody is necessary to define an "epitope" (page 937, column 2). According to Greenspan et al., an epitope will include residues that make contacts with a ligand, here the antibody, but are energetically neutral, or even destabilizing to binding. Furthermore, an epitope will not include any residue not contacted by the antibody, even though substitution of such a residue might profoundly affect binding. Accordingly, it follows that the immunoepitopes that can bind to a given polypeptide can only be identified empirically. Therefore, absent a detailed and particular description of a representative number, or at least a substantial number of the members of the genus of immunoepitopes and framework regions, the skilled artisan could not immediately recognize or distinguish members of the claimed genus of antibodies (and hence the nucleic acids encoding them).
While the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains and surrounding framework regions of antibodies. For example, Giusti et al. (Proc. Natl. Acad. Sci. USA. 1987 May; 84 (9): 2926-2930) teaches the specificity and affinity of an antibody is exquisitely sensitive to amino acid substitutions within the primary structure of the antibody, since only a single amino acid substitution in the heavy chain of an antibody completely altered the binding specificity of an antibody that binds phosphocholine, such that the altered antibody fails to bind phosphocholine but instead binds DNA (see entire document [e.g., the abstract]). This unpredictability of single amino acid changes in an antibody is underscored by Winkler et al (J. Imm., 265:4505-4514, 2000) who teach that single amino acid changes in antibody side chains can result in unpredictable and substantial changes in antibody specificity; (see entire document [e.g., the abstract]). Chien et al. (Proc. Natl. Acad. Sci. USA. 1989 Jul; 86 (14): 5532-5536) teaches that significant structural and functional changes in an antigen-binding site can be caused by amino acid substitutions in the primary structure of an antibody, including substitutions at a site remote from the complementarity determining regions of the antigen-binding domain; (see entire document [e.g., the abstract]). Similarly, but more recently, Caldas et al. (Mol. Immunol. 2003 May; 39 (15): 941-952) teaches an unexpected effect of substituting a framework residue upon binding specificity during the humanization of an antibody that binds CD18 (see entire document [e.g., the abstract]). Casadevall et al. (PNAS, Vol 109 No. 31, pages 12272-12273) underscores the importance of the framework regions with regard to antibody affinity and binding specificity.
Sela-Culang et al. (Frontiers in Immunology, 2013 Vol. 4, article 302, pages 1-13) clearly set forth the role of CDRs, framework regions and constant regions in antibody specificity and affinity. Sela-Culang et al. disclose that the belief CDRs of an antibody are responsible for antigen recognition while the constant domains mediate effector activation is an oversimplification and that some residues within the CDRs never participate in antigen binding while some off-CDR residues are critical for antigen interaction. Sela-Culang et al. further disclose that only 20-33% of the residues within the CDRs actually participate in antigen binding (see page 4) and that it is well established that some of the framework (FR) residues play an important role in antigen binding (see page 7). This point is demonstrated by the fact that humanizing an antibody by grafting only the CDRs usually results in a significant drop or complete loss of antigen binding. Sela-Culang et al. also discloses that the framework region residues that affect binding can be divided into two categories: those that contact the antigen (which can be close in sequence to the CDRs or far from the CDRs in sequence but are in close proximity to it in 3-D structure) and those that are not in contact with the antigen but affect antigen binding indirectly (which can be in spatial proximity to the CDRs and those that are not). The framework regions residues that are more distant from the paratope (i.e. binding residues) not only play a role in maintaining the overall structure of the Fv domains but may affect antigen binding itself by directing the relative orientation of the VH with relation to the VL and thus the orientation of the CDRs relative to each other (see page 7). Specific knowledge of the FR residues involved in antigen binding is critical for antibody design in general and for the humanization of antibodies in particular. Finally, Sela-Culang et al. disclose that the constant regions of antibodies play a role in antigen binding due to an allosteric influence of the constant domains on the structure of the variable domains as evidenced by the differences in affinity and specificities of antibodies with the same variable region but different isotypes. (see page 8).
Recently, describing antibodies by their functions was addressed in the Centocor decision (CENTOCOR ORTHO BIOTECH, INC. v ABBOTT LABORATORIES (Fed Cir, 2010-1144, 2/23/2011)). In said case the court stated”
To satisfy the written description requirement, "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,' and demonstrate that by disclosure in the specification of the patent." Carnegie Mellon Univ. v. Hoffmann-La Roche Inc., 541 F.3d 1115, 1122 (Fed. Cir. 2008) (quoting Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563-64 (Fed. Cir. 1991)). Assessing such "possession as shown in the disclosure" requires "an objective inquiry into the four corners of the specification." Ariad, 598 F.3d at 1351. Ultimately, "the specification must describe an invention understandable to [a person of ordinary skill in the art] and show that the inventor actually invented the invention claimed." Id. A "mere wish or plan" for obtaining the claimed invention is not adequate written description. Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559, 1566 (Fed. Cir. 1997).
The court further opined that Centocor's suggestion
that our decision in Noelle and the PTO written description guidelines support the view that fully disclosing the human TNF-α protein provides adequate written description for any antibody that binds to human TNF-α. That suggestion is based on an unduly broad characterization of the guidelines and our precedent.
The court concluded that
While our precedent suggests that written description for certain antibody claims can be satisfied by disclosing a well-characterized antigen, that reasoning applies to disclosure of newly characterized antigens where creation of the claimed antibodies is routine. Claiming 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.
Moreover, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) recently 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. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen" test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone 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.
Even more recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) recently decided (and was unanimously affirmed by the U.S. Supreme Court) Amgen v. Sanofi, Aventisub LLC, 987 F.3d 1080, 2021 U.S.P.Q.2d 169 (Fed. Cir. 2021), which concerned enablement for claims drawn to antibodies. While said case was dealt with enablement it should be noted that:
One of Amgen's expert witnesses admitted that translating an antibody's amino acid "sequence into a known three-dimensional structure is still not possible." J.A. 3910; see also Decision, 2019 U.S. Dist. LEXIS 146305 , at *9 . Another of Amgen's experts conceded that "substitutions in the amino acid sequence of an antibody can affect the antibody's function, and testing would be required to ensure that a substitution does not alter the binding and blocking functions." J.A. 3891; see also Decision, 2019 U.S. Dist. LEXIS 146305 , at *9 .
Said expert testimony illustrates the unpredictability of the antibody arts and clearly sets forth the expectations of the skilled artisan.
Therefore, because the art is unpredictable, in accordance with the MPEP, the description of immunoepitopes (arrangement of immunoepitopes and CDRs and framework regions) is not deemed representative of the genus of antibodies to which the claims refer. Consequently, only nucleic acids encoding the 319-44mod1 antibody (i.e. the nucleic acid of SEQ ID NO:1 and the amino acid sequence of SEQ ID NO:2), but not the full breadth of the claims meets the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
35 USC § 112, Scope of Enablement
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.
The rejection of claims 1-6, 9-10 and 18 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for nucleic acids encoding the DMab 319-44mod1 (with the amino acid sequence of SEQ ID NO:2 or with the nucleic acid sequence of SEQ ID NO:1), does not reasonably provide enablement for nucleic acids encoding variants of said antibody that bind to an undefined OspA is maintained for reasons of record.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
The specification is insufficient to enable one skilled in the art to practice the invention as claimed without an undue amount of experimentation. Undue experimentation must be considered in light of factors including: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill in the art, the level of predictability of the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention, see In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
Applicant argues:
1. Applicants note that the MPEP at §2164.06 provides that "[a] specification may call for a reasonable amount of experimentation to make and use a claimed invention, and reasonableness in any case will depend on the nature of the invention and the underlying art." Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 596, 2023 USPQ2d 602 (2023). The quantity of experimentation needed to be performed by one skilled in the art is only one factor involved in determining whether "undue experimentation" is required to make and use the invention. "[A]n extended period of experimentation may not be undue if the skilled artisan is given sufficient direction or guidance." In re Colianni, 561 F.2d 220, 224, 195 USPQ 150, 153 (CCPA 1977). "'The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed."' In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) (citing In re Angstadt, 537 F.2d 498, 502-04, 190 USPQ 214, 217-19 (CCPA 1976)).
2. Claim 1 to has been amended to recite "[a] nucleic acid molecule encoding one or more synthetic antibodies, wherein the nucleic acid molecule encodes at least one amino acid sequence selected from the group consisting of a) the amino acid sequence as set forth in SEQ ID NO:2; and b) a functional fragment of the amino acid sequence as set forth in SEQ ID NO:2; or wherein the nucleic acid molecule comprises at least one nucleotide sequence selected from the group consisting of a) the nucleotide sequence as set forth SEQ ID NO: 1; and b) a functional fragment of the nucleotide sequence as set forth in SEQ ID NO: 1; or wherein the nucleic acid molecule comprises a nucleotide sequence encoding a variable heavy chain region and a variable light chain region, wherein the sequence encoding a variable heavy chain region is selected from the group consisting of: a) a nucleotide sequence encoding the amino acid sequence as set forth in SEQ ID NO:4; b) the nucleotide sequence as set forth in SEQ ID NO:3; and wherein the sequence encoding a variable light chain region is selected from the group consisting of: a) a nucleotide sequence encoding the amino acid sequence as set forth in SEQ ID NO:6; b) the nucleotide sequence as set forth in SEQ ID NO:5; and wherein the one or more synthetic antibodies binds to the OspA protein."
3. Claim 3 has been amended to recite "group consisting of a) the amino acid sequence as set forth in SEQ ID NO:2; and b) a functional fragment of the amino acid sequence as set forth SEQ ID NO:2."
4. Claim 4 has been amended to recite "group consisting of a) the nucleotide sequence as set forth in SEQ ID NO: 1; and b) a functional fragment of the nucleotide sequence as set forth in SEQ ID NO:1.".
5. Claim 5 has been amended to recite "group consisting of: a) a nucleotide sequence encoding the amino acid sequence as set forth in SEQ ID NO:4; and b) the nucleotide sequence as set forth in SEQ ID NO:3 and wherein the sequence encoding a variable light chain region is selected from the group consisting of: a) a nucleotide sequence encoding the amino acid sequence as set forth in SEQ ID NO:6; and b) the nucleotide sequence as set forth in SEQ ID NO:5.".
6. The instant specification details the specific sequences, i.e., structural chemical formulas, with which the skilled artisan can construct the synthetic OspA antibody (e.g., paragraphs [0007]-[0008], [0019], [0021], [00104]-[00108], [00161], and [00222]); provides direction on how to modify the antibody appropriately (e.g., paragraphs [00181]-[00184]); teaches how to use it to perform the biological function of binding to the OspA protein (e.g., paragraphs [00194] and [00202]); and demonstrates how to evaluate successful production of a synthetic antibody that performs the biological function of binding to or reacting with the OspA protein (e.g., paragraphs [0042], [0043], [00202], [00239], [00240], Figures 6C and 7B, and Example 1).
7. The level of skill and readily available knowledge in the art with respect to antibodies is high. Accordingly, one skilled in the art can readily obtain functional fragments of the claimed antibodies. Further, the ability of such antibodies to bind the OspA protein can be readily assessed through the direction of the instant Specification (See, e.g., Example 1).
Applicant’s arguments have been fully considered and deemed non-persuasive.
With regard to Points 1-7, the amendments to claims 1 and 3-5 is insufficient to overcome the rejection. As set forth in the rejection, the unpredictability of the art regarding the was clearly summarized by Sir Gregory Paul Winter et al. as Amici Curiae, (submitted February 10, 2023, to the Supreme Court in Amgen Inc., et al., v. Sanofi, et al.) when he writes:
“Amgen’s expert further agreeing that even if antibody sequences were “similar”, that doesn’t tell you whether or not—whether an antibody binds to a particular region on a particular protein.” and further opines that “while it can be fairly said that an antibodies sequence determines its structure, which determines it function, an antibody scientist is unable to predict the function of an antibody from its sequence. Furthermore, an antibody scientist is unable to accurately predict how a change in the amino acid sequence of an antibody of known function may affect that function. The only way to know the function of a given antibody is to test it once it has been made.” (see page 15 of brief).
Recently the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, Aventisub LLC, 987 F.3d 1080, 2021 U.S.P.Q.2d 169 (Fed.
Cir. 2021), which concerned enablement 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. The court opined:
Wands did not proclaim that all broad claims to antibodies are necessarily enabled. Facts control and, in this court, so does the standard of review. In considering the Wands factors, the district court compared the present case to other cases in which we found lack of enablement due to the undue experimentation required to make and use the full scope of the claimed compounds that require a particular structure and functionality. For example, in Wyeth & Cordis Corp. v. Abbott Laboratories, we held that claims covering methods of preventing restenosis with compounds having certain functionality requirements were invalid for lack of enablement. See 720 F.3d 1380 , 1385-86 (Fed. Cir. 2013). Of particular significance, we held that due to the large number of possible candidates within the scope of the claims and the specification's corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the claimed functionality.
The court further stated:
In cases involving claims that state certain structural requirements and also require performance of some function (e.g., efficacy for a certain purpose), we have explained that undue experimentation can include undue experimentation in identifying, from among the many concretely identified compounds that meet the structural requirements, the compounds that satisfy the functional requirement. Id. at 1100 n.2 (citations omitted).
That reasoning applies here. While functional claim limitations are not necessarily precluded in claims that meet the enablement requirement, such limitations pose high hurdles in fulfilling the enablement requirement for claims with broad functional language. See, e.g., Wyeth, 720 F.3d at 1384 (finding that practicing the full scope of the claims would require excessive experimentation); Enzo, 928 F.3d at 1345 (finding that the specification failed to teach whether the many embodiments would be both hybridizable and detectable upon hybridization); Idenix, 941 F.3d at 1155-56 (finding that the broad functional limitation of having efficacy against hepatitis C virus increased the number of nucleoside candidates that would need to be screened).
We also agree with the district court that this invention is in an unpredictable field of science with respect to satisfying the full scope of the functional limitations. One of Amgen's expert witnesses admitted that translating an antibody's amino acid "sequence into a known three-dimensional structure is still not possible." J.A. 3910; see also Decision, 2019 U.S. Dist. LEXIS 146305 , at *9 . Another of Amgen's experts conceded that "substitutions in the amino acid sequence of an antibody can affect the antibody's function, and testing would be required to ensure that a substitution does not alter the binding and blocking functions." J.A. 3891; see also Decision, 2019 U.S. Dist. LEXIS 146305 , at *9 . And while some need for testing by itself might not indicate a lack of enablement, we note here the conspicuous absence of nonconclusory evidence that the full scope of the broad claims can [*1088] predictably be generated by the described methods. Instead, we have evidence only that a small subset of examples of antibodies can predictably be generated.
Although the specification provides some guidance, including data regarding certain embodiments, we agree with the district court that "[a]fter considering the disclosed roadmap in light of the unpredictability of the art, any reasonable factfinder would conclude that the patent does not provide significant guidance or direction to a person of ordinary skill in the art for the full scope of the claims." Decision, 2019 U.S. Dist. LEXIS 146305 , at *11 . Here, even assuming that the patent's "roadmap" provided guidance for making antibodies with binding properties similar to those of the working examples, no reasonable factfinder could conclude that there was adequate guidance beyond the narrow scope of the working examples that the patent's "roadmap" produced.
The decision set forth:
One of Amgen's expert witnesses admitted that translating an antibody's amino acid "sequence into a known three-dimensional structure is still not possible." J.A. 3910; see also Decision, 2019 U.S. Dist. LEXIS 146305 , at *9 . Another of Amgen's experts conceded that "substitutions in the amino acid sequence of an antibody can affect the antibody's function, and testing would be required to ensure that a substitution does not alter the binding and blocking functions." J.A. 3891; see also Decision, 2019 U.S. Dist. LEXIS 146305 , at *9 .
The court concluded:
As the district court noted, the only ways for a person of ordinary skill to discover undisclosed claimed embodiments would be through either "trial and error, by making changes to the disclosed antibodies and then screening those antibodies for the desired binding and blocking properties," or else "by discovering the antibodies de novo" according to a randomization-and-screening "roadmap." Id. Either way, we agree with the district court that the required experimentation "would take a substantial [**8] amount of time and effort." 2019 U.S. Dist. LEXIS 146305, at *12. We do not hold that the effort required to exhaust a genus is dispositive. It is appropriate, however, to look at the amount of effort needed to obtain embodiments outside the scope of the disclosed examples and guidance. The functional limitations here are broad, the disclosed examples and guidance are narrow, and no reasonable jury could conclude under these facts that anything but "substantial time and effort" would be required to reach the full scope of claimed embodiments.
In Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court, held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR. Similarly, the instant claims are drawn to a vast genus of antibodies that bind to a OspA with no defined sequence and wherein only a portion of the specific structure is defined. Given, that there is no limitation regarding to the antibody’s sequence other than percent identity to a baseline sequence, no “specific structure” is defined by the claims as set forth by the Supreme Court. This is analogous to the fact pattern in the aforementioned Amgen case where Amgen argued that one could arrive at all the other antibodies by “conservative substitution” (in their citing of Morphosys AG v. Janssen Biotech). The Supreme Court specifically addressed this in the Amgen decision where they wrote:
“The second method is what Amgen calls “conservative substitution.” Id., at 14, 17. This technique requires scientists to: (1) start with an antibody known to perform the described functions; (2) replace select amino acids in the antibody with other amino acids known to have similar properties; and (3) test the resulting antibody to see if it also performs the described functions. See id., at 14–15.”
And further opined:
“Still, it says, its broad claims are enabled because scientists can make and use every undisclosed but functional antibody if they simply follow the company’s “roadmap” or its proposal for “conservative substitution.” We cannot agree. These two approaches amount to little more than two research assignments. The first merely describes step-by-step Amgen’s own trial-and-error method for finding functional antibodies—calling on scientists to create a wide range of candidate antibodies and then screen each to see which happen to bind to PCSK9 in the right place and block it from binding to LDL receptors. See Part I–B, supra; 987 F. 3d, at 1088; 2019 WL 4058927, *10–*13. The second isn’t much different. It requires scientists to make substitutions to the amino acid sequences of antibodies known to work and then test the resulting antibodies to see if they do too—an uncertain prospect given the state of the art. See Parts I–A, I–B, supra; 987 F. 3d, at 1088; 2019 WL 4058927, *10–*13.”
Given, the that the court found that making conservative substitutions within full disclosed antibody sequence (i.e. the 26 full length antibodies disclosed in Amgen) constituted undue experimentation, utilizing said method with only a partial antibody sequence would be even more “undue”.
Additionally, the Court clarified that the specification does not always need to "describe with particularity how to make and use every single embodiment within a claimed class." Id. at 610-11. However, "[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class….The more one claims, the more one must enable." Id.
The Court also set forth that the specification may require a reasonable amount of experimentation to make and use the invention and what is reasonable will depend on the nature of the invention and the underlying art. Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 596, 2023 USPQ2d 602 (2023). For example, "it may suffice to give an example (or a few examples) if the specification also discloses some general quality . . . running through the class that gives it a peculiar fitness for the particular purpose" and "disclosing that general quality may reliably enable a person skilled in the art to make and use all of what is claimed, not merely a subset." Id. at 611 (internal quotations omitted). However, while the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class which included "a ‘vast’ number of additional antibodies" that Amgen had not described by their amino acid sequences. Id. at 613. The Court found that Amgen sought to monopolize an entire class by their function, even though that class was much broader than the 26 exemplary antibodies disclosed by their amino acid structure. Id. at 613. In Amgen Inc. v. Sanofi, Aventisub LLC, 987 F.3d 1080 (Fed. Cir. 2021), which the Supreme Court affirmed, the Federal Circuit explicitly applied the Wands factors to assess whether the specification of Amgen’s patent provided sufficient enablement, for purposes of 35 U.S.C. 112(a), to make and use the full scope of the claimed invention. The court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. See also the following cases across various technology areas: McRO, Inc. v. Bandai Namco Games Am. Inc., 959 F.3d 1091, 2020 USPQ2d 10550 (Fed. Cir. 2020); Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380, 107 USPQ2d 1273 (Fed. Cir. 2013); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340 (Fed. Cir. 2019); and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149, 2019 USPQ2d 415844 (Fed. Cir. 2019). In the instant case the specification discloses a limited number of variants of the 4C10 antibody wherein all variations were within the CDRs. No antibodies with variation in any other portion of the 4C10 antibody were disclosed.
Therefore the Amgen decisions clearly set forth that claiming an antibody by partial structure and function is not enabling even when preparation of such an antibody is routine and conventional. Consequently, the specification, while being enabling for the nucleic acids encoding 319-44mod1 antibody (i.e. the nucleic acid of SEQ ID NO:1 and the amino acid sequence of SEQ ID NO:2), does not reasonably provide enablement for the claimed genus of variant antibodies and fragments thereof.
As set forth previously, In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) states, “The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.” “The “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling” (MPEP 2164.03). The MPEP further states that physiological activity can be considered inherently unpredictable. With these teachings in mind, an enabling disclosure, commensurate in scope with the breadth of the claimed invention, is required.
the instant claims are drawn to nucleic acids encoding antibodies that bind to an undefined OspA wherein said antibodies comprise one or more sequences based on SEQ ID NO:1-6 (or fragments thereof). The specification discloses a single antibody DMab 319-44mod1 that binds OspA and contains the recited sequence. This antibody (and hence the nucleic acid encoding it) is fully enabled. However, the aforementioned claims are directed to encompass all antibody variants of SEQ ID NO:1 and SEQ ID NO:2 as well as any antibody that contain the recited heavy and/or light chains (and variants thereof). The specification is not enabling for any of these antibodies as it is silent as to what combination of sequences result in a given antibody to bind to a given OspA.
The specification fails to disclose what combination of recited sequences (or fragments thereof) that result in OspA and the other aforementioned immunological characteristics. As evidenced by the teachings of Skolnick et al., the art is unpredictable. Skolnick et al. (Trends in Biotechnology 18: 34-39, 2000) discloses the skilled artisan is well aware that assigning functional activities for any particular protein or protein family based upon sequence homology is inaccurate, in part because of the multifunctional nature of proteins (see, e.g., the abstract; and page 34, Sequence-based approaches to function prediction). Even in situations where there is some confidence of a similar overall structure between two proteins, only experimental research can confirm the artisan's best guess as to the function of the structurally related protein (see, in particular, the abstract and Box 2). Thus, one skilled in the art would not accept the assertion, which is based only upon an observed similarity in amino acid sequence that a variant of a given polypeptide would necessarily bind to a given antibody. Moreover, as evidenced by Greenspan et al. (Nature Biotechnology 7: 936-937, 1999), defining epitopes is not as easy as it seems. Greenspan et al. recommends defining an epitope by the structural characterization of the molecular interface between the antigen and the antibody is necessary to define an "epitope" (page 937, column 2). According to Greenspan et al., an epitope will include residues that make contacts with a ligand, here the antibody, but are energetically neutral, or even destabilizing to binding. Furthermore, an epitope will not include any residue not contacted by the antibody, even though substitution of such a residue might profoundly affect binding. Accordingly, it follows that the immunoepitopes that can elicit antibodies that bind to a given antigen can only be identified empirically. Therefore, absent a detailed and particular description of a representative number, or at least a substantial number of the members of the genus of immunoepitopes, the skilled artisan could not immediately recognize or distinguish members of the claimed genus of antibodies. It is well settled that the exchanging of CDRs among between antibodies is not predictable. While the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains and surrounding framework regions of antibodies. For example, Giusti et al. (Proc. Natl. Acad. Sci. USA. 1987 May; 84 (9): 2926-2930) teaches the specificity and affinity of an antibody is exquisitely sensitive to amino acid substitutions within the primary structure of the antibody, since only a single amino acid substitution in the heavy chain of an antibody completely altered the binding specificity of an antibody that binds phosphocholine, such that the altered antibody fails to bind phosphocholine but instead binds DNA (see entire document [e.g., the abstract]). This unpredictability of single amino acid changes in an antibody is underscored by Winkler et al (J. Imm., 265:4505-4514, 2000) who teach that single amino acid changes in antibody side chains can result in unpredictable and substantial changes in antibody specificity; (see entire document [e.g., the abstract]). Chien et al. (Proc. Natl. Acad. Sci. USA. 1989 Jul; 86 (14): 5532-5536) teaches that significant structural and functional changes in an antigen-binding site can be caused by amino acid substitutions in the primary structure of an antibody, including substitutions at a site remote from the complementarity determining regions of the antigen-binding domain; (see entire document [e.g., the abstract]). Similarly, but more recently, Caldas et al. (Mol. Immunol. 2003 May; 39 (15): 941-952) teaches an unexpected effect of substituting a framework residue upon binding specificity during the humanization of an antibody that binds CD18 (see entire document [e.g., the abstract]). Casadevall et al. (PNAS, Vol 109 No. 31, pages 12272-12273) underscores the importance of the framework regions with regard to antibody affinity and binding specificity.
Additionally, Jones et al. (Letters to Nature, Vol. 321, pages 522-525) disclose that:
“The culture supernatants of several gpt+ clones were assayed by radioimmunoassay and found to contain NIP-cap-binding antibody. The antibody secreted by one such clone was purified from the culture supernatant by affinity chromatography on NIP-cap-Sepharose, and by SDS-polyacrylamide gel electrophoresis the protein was indistinguishable from the mouse chimeric MVNP+IgE”. (see page 523).
Clearly demonstrating that they were not able to “predict” the activity of a given antibody construct. Additionally, Queen et al. (PNAS, Vol. 86, pages 10029-10033) disclose that they had to construct models (via a computer program) to determine which portions of the murine FR regions must be maintained in order to preserve antibody binding as resides outside the CDRs can “either influence their conformation or interact directly with the antigen” (see page 10031). Again, Queen et al. had to screen a multitude of clones and empirically test them for binding activity (see page 10032). The art is replete with examples demonstrating that the unpredictability in determining antibody specificity and affinity. For example:
Winters and Harris (Immunology Today 14: 243-246, 1993) clearly set forth that when humanizing a murine antibody one needs to consider the interactions between the framework regions and the CDR loops and that all their “humanized antibodies” had to be empirically tested for specificity and affinity.
Moon et al. (Mol. Cells 39(3): 217-228, 2016) clearly state that “…residues that do not interact or contact antigen directly influence the interaction between the heavy and light chain, and thus increase binding affinity.”. This supports the Examiner’s position as if a change in the framework residues of an antibody can lead to an increase in binding affinity the converse is equally true (i.e. the change can lead to a decrease or ablation of binding and/or affinity). Moreover, it should be noted that Moon et al. was not able to predict which mutations would have a given effect. They had to utilize phage screening methods to determine which “mutants” maintained binding specificity.
Bendig et al. ("Humanization of Rodent Monoclonal Antibodies by CDR Grafting," Methods: A Companion to Methods in Enzymology, 8: 83-93, 1995) disclose a step-by-step process for making humanized antibodies using just the CDRs from a rodent antibody clearly states “In many cases, a rodent antibody that is humanized in a simple CDR graft will show little or no binding to antigen. It is important to study the amino acids of the human FRs to determine whether any of the amino acids are likely to adversely influence binding to the antigen, either directly through interactions with the antigen or indirectly by altering the positioning of the CDR loops” (see page 86). Again, as with all of the cited references, all of Bendig’s humanized antibodies had to be empirically tested for specificity and affinity.
Finally, Sela-Culang et al. (Frontiers in Immunology, 2013 Vol. 4, article 302, pages 1-13) clearly set forth the role of CDRs, framework regions and constant regions in antibody specificity and affinity. Sela-Culang et al. disclose that the belief CDRs of an antibody are solely responsible for antigen recognition while the constant domains mediate effector activation is an oversimplification as some residues within the CDRs never participate in antigen binding while some off-CDR residues are critical for antigen interaction. Sela-Culang et al. further disclose that only 20-33% of the residues within the CDRs actually participate in antigen binding (see page 4) and that it is well established that some of the framework (FR) residues play an important role in antigen binding (see page 7). This point is demonstrated by the fact that humanizing an antibody by grafting only the CDRs usually results in a significant drop or complete loss of antigen binding. Sela-Culang et al. also discloses that the framework region residues that affect binding can be divided into two categories: those that contact the antigen (which can be close in sequence to the CDRs or far from the CDRs in sequence but are in close proximity to it in 3-D structure) and those that are not in contact with the antigen but affect antigen binding indirectly (which can be in spatial proximity to the CDRs and those that are not). The framework regions residues that are more distant from the paratope (i.e. binding residues) not only play a role in maintaining the overall structure of the Fv domains but may affect antigen binding itself by directing the relative orientation of the VH with relation to the VL and thus the orientation of the CDRs relative to each other (see page 7). Specific knowledge of the FR residues involved in antigen binding is critical for antibody design in general and for the humanization of antibodies in particular. Finally, Sela-Culang et al. disclose that the constant regions of antibodies play a role in antigen binding due to an allosteric influence of the constant domains on the structure of the variable domains as evidenced by the differences in affinity and specificities of antibodies with the same variable region but different isotypes. (see page 8).
The unpredictability of the art regarding the was clearly summarized by Sir Gregory Paul Winter et al. as Amici Curiae, (submitted February 10, 2023, to the Supreme Court in Amgen Inc., et al., v. Sanofi, et al.) when he writes:
“Amgen’s expert further agreeing that even if antibody sequences were “similar”, that doesn’t tell you whether or not—whether an antibody binds to a particular region on a particular protein.” and further opines that “while it can be fairly said that an antibodies sequence determines its structure, which determines it function, an antibody scientist is unable to predict the function of an antibody from its sequence. Furthermore, an antibody scientist is unable to accurately predict how a change in the amino acid sequence of an antibody of known function may affect that function. The only way to know the function of a given antibody is to test it once it has been made.” (see page 15 of brief).
Recently the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, Aventisub LLC, 987 F.3d 1080, 2021 U.S.P.Q.2d 169 (Fed.
Cir. 2021), which concerned enablement 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. The court opined:
Wands did not proclaim that all broad claims to antibodies are necessarily enabled. Facts control and, in this court, so does the standard of review. In considering the Wands factors, the district court compared the present case to other cases in which we found lack of enablement due to the undue experimentation required to make and use the full scope of the claimed compounds that require a particular structure and functionality. For example, in Wyeth & Cordis Corp. v. Abbott Laboratories, we held that claims covering methods of preventing restenosis with compounds having certain functionality requirements were invalid for lack of enablement. See 720 F.3d 1380 , 1385-86 (Fed. Cir. 2013). Of particular significance, we held that due to the large number of possible candidates within the scope of the claims and the specification's corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the claimed functionality.
The court further stated:
In cases involving claims that state certain structural requirements and also require performance of some function (e.g., efficacy for a certain purpose), we have explained that undue experimentation can include undue experimentation in identifying, from among the many concretely identified compounds that meet the structural requirements, the compounds that satisfy the functional requirement. Id. at 1100 n.2 (citations omitted).
That reasoning applies here. While functional claim limitations are not necessarily precluded in claims that meet the enablement requirement, such limitations pose high hurdles in fulfilling the enablement requirement for claims with broad functional language. See, e.g., Wyeth, 720 F.3d at 1384 (finding that practicing the full scope of the claims would require excessive experimentation); Enzo, 928 F.3d at 1345 (finding that the specification failed to teach whether the many embodiments would be both hybridizable and detectable upon hybridization); Idenix, 941 F.3d at 1155-56 (finding that the broad functional limitation of having efficacy against hepatitis C virus increased the number of nucleoside candidates that would need to be screened).
We also agree with the district court that this invention is in an unpredictable field of science with respect to satisfying the full scope of the functional limitations. One of Amgen's expert witnesses admitted that translating an antibody's amino acid "sequence into a known three-dimensional structure is still not possible." J.A. 3910; see also Decision, 2019 U.S. Dist. LEXIS 146305 , at *9 . Another of Amgen's experts conceded that "substitutions in the amino acid sequence of an antibody can affect the antibody's function, and testing would be required to ensure that a substitution does not alter the binding and blocking functions." J.A. 3891; see also Decision, 2019 U.S. Dist. LEXIS 146305 , at *9 . And while some need for testing by itself might not indicate a lack of enablement, we note here the conspicuous absence of nonconclusory evidence that the full scope of the broad claims can [*1088] predictably be generated by the described methods. Instead, we have evidence only that a small subset of examples of antibodies can predictably be generated.
Although the specification provides some guidance, including data regarding certain embodiments, we agree with the district court that "[a]fter considering the disclosed roadmap in light of the unpredictability of the art, any reasonable factfinder would conclude that the patent does not provide significant guidance or direction to a person of ordinary skill in the art for the full scope of the claims." Decision, 2019 U.S. Dist. LEXIS 146305 , at *11 . Here, even assuming that the patent's "roadmap" provided guidance for making antibodies with binding properties similar to those of the working examples, no reasonable factfinder could conclude that there was adequate guidance beyond the narrow scope of the working examples that the patent's "roadmap" produced.
The decision set forth:
One of Amgen's expert witnesses admitted that translating an antibody's amino acid "sequence into a known three-dimensional structure is still not possible." J.A. 3910; see also Decision, 2019 U.S. Dist. LEXIS 146305 , at *9 . Another of Amgen's experts conceded that "substitutions in the amino acid sequence of an antibody can affect the antibody's function, and testing would be required to ensure that a substitution does not alter the binding and blocking functions." J.A. 3891; see also Decision, 2019 U.S. Dist. LEXIS 146305 , at *9 .
The court concluded:
As the district court noted, the only ways for a person of ordinary skill to discover undisclosed claimed embodiments would be through either "trial and error, by making changes to the disclosed antibodies and then screening those antibodies for the desired binding and blocking properties," or else "by discovering the antibodies de novo" according to a randomization-and-screening "roadmap." Id. Either way, we agree with the district court that the required experimentation "would take a substantial [**8] amount of time and effort." 2019 U.S. Dist. LEXIS 146305, at *12. We do not hold that the effort required to exhaust a genus is dispositive. It is appropriate, however, to look at the amount of effort needed to obtain embodiments outside the scope of the disclosed examples and guidance. The functional limitations here are broad, the disclosed examples and guidance are narrow, and no reasonable jury could conclude under these facts that anything but "substantial time and effort" would be required to reach the full scope of claimed embodiments.
In Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court, held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR. Similarly, the instant claims are drawn to a vast genus of antibodies that bind to a OspA with no defined sequence and wherein only a portion of the specific structure is defined. Given, that there is no limitation regarding to the antibody’s sequence other than percent identity to a baseline sequence, no “specific structure” is defined by the claims as set forth by the Supreme Court. This is analogous to the fact pattern in the aforementioned Amgen case where Amgen argued that one could arrive at all the other antibodies by “conservative substitution” (in their citing of Morphosys AG v. Janssen Biotech). The Supreme Court specifically addressed this in the Amgen decision where they wrote:
“The second method is what Amgen calls “conservative substitution.” Id., at 14, 17. This technique requires scientists to: (1) start with an antibody known to perform the described functions; (2) replace select amino acids in the antibody with other amino acids known to have similar properties; and (3) test the resulting antibody to see if it also performs the described functions. See id., at 14–15.”
And further opined:
“Still, it says, its broad claims are enabled because scientists can make and use every undisclosed but functional antibody if they simply follow the company’s “roadmap” or its proposal for “conservative substitution.” We cannot agree. These two approaches amount to little more than two research assignments. The first merely describes step-by-step Amgen’s own trial-and-error method for finding functional antibodies—calling on scientists to create a wide range of candidate antibodies and then screen each to see which happen to bind to PCSK9 in the right place and block it from binding to LDL receptors. See Part I–B, supra; 987 F. 3d, at 1088; 2019 WL 4058927, *10–*13. The second isn’t much different. It requires scientists to make substitutions to the amino acid sequences of antibodies known to work and then test the resulting antibodies to see if they do too—an uncertain prospect given the state of the art. See Parts I–A, I–B, supra; 987 F. 3d, at 1088; 2019 WL 4058927, *10–*13.”
Given, the that the court found that making conservative substitutions within full disclosed antibody sequence (i.e. the 26 full length antibodies disclosed in Amgen) constituted undue experimentation, utilizing said method with only a partial antibody sequence would be even more “undue”.
Additionally, the Court clarified that the specification does not always need to "describe with particularity how to make and use every single embodiment within a claimed class." Id. at 610-11. However, "[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class….The more one claims, the more one must enable." Id.
The Court also set forth that the specification may require a reasonable amount of experimentation to make and use the invention and what is reasonable will depend on the nature of the invention and the underlying art. Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 596, 2023 USPQ2d 602 (2023). For example, "it may suffice to give an example (or a few examples) if the specification also discloses some general quality . . . running through the class that gives it a peculiar fitness for the particular purpose" and "disclosing that general quality may reliably enable a person skilled in the art to make and use all of what is claimed, not merely a subset." Id. at 611 (internal quotations omitted). However, while the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class which included "a ‘vast’ number of additional antibodies" that Amgen had not described by their amino acid sequences. Id. at 613. The Court found that Amgen sought to monopolize an entire class by their function, even though that class was much broader than the 26 exemplary antibodies disclosed by their amino acid structure. Id. at 613. In Amgen Inc. v. Sanofi, Aventisub LLC, 987 F.3d 1080 (Fed. Cir. 2021), which the Supreme Court affirmed, the Federal Circuit explicitly applied the Wands factors to assess whether the specification of Amgen’s patent provided sufficient enablement, for purposes of 35 U.S.C. 112(a), to make and use the full scope of the claimed invention. The court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. See also the following cases across various technology areas: McRO, Inc. v. Bandai Namco Games Am. Inc., 959 F.3d 1091, 2020 USPQ2d 10550 (Fed. Cir. 2020); Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380, 107 USPQ2d 1273 (Fed. Cir. 2013); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340 (Fed. Cir. 2019); and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149, 2019 USPQ2d 415844 (Fed. Cir. 2019). In the instant case the specification discloses a limited number of variants of the 4C10 antibody wherein all variations were within the CDRs. No antibodies with variation in any other portion of the 4C10 antibody were disclosed.
Therefore the Amgen decisions clearly set forth that claiming an antibody by partial structure and function is not enabling even when preparation of such an antibody is routine and conventional. Consequently, the specification, while being enabling for the nucleic acids encoding 319-44mod1 antibody (i.e. the nucleic acid of SEQ ID NO:1 and the amino acid sequence of SEQ ID NO:2), does not reasonably provide enablement for the claimed genus of variant antibodies based on a multiplicity of the sequences of SEQ ID NO:1-6 (and fragments thereof).
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/ROBERT A ZEMAN/Primary Examiner, Art Unit 1645 February 11, 2026