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 10-25-2024 is acknowledged. Claim 1 has been amended.
Claims 13 and 16 have been canceled. Claims 1-3, 5-7, 9-11, 14, 17-19, 21, 23-24 and 29-31 are pending. Claims 17-19, 21, 23-24 and 29-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1-3, 5-7, 9-11 and 14 are currently under examination.
Information Disclosure Statement
The Information Disclosure Statements filed on 10-25-2024 and 2-13-2025 have been considered. Initialed copies are attached hereto.
It should be noted that 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
The substitute specification, filed 2/6/2025 has been entered.
Nucleotide and/or Amino Acid Sequence Disclosures
The specification is deemed to be in compliance with 37 CFR 1.821(d) in light of the amendment thereto.
Objections Withdrawn
The objection to the specification because it contains an embedded hyperlink and/or other form of browser-executable code is withdrawn in light of the amendment thereto.
Claim Objections
The objection to claims 1-3, 5-7, 9-11, 13-14, 16 for reciting claim language drawn to a non-elected invention is maintained.
Claim Rejections Withdrawn
The rejection of claim 5 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement (biological deposit) requirement is withdrawn.
The rejection of claims 1-3, 6-7, 9-11, 13-14 and 16 under 35 U.S.C. 102(a)(1) as being anticipated by Altintas et al. (WO 2018/011421 – IDS filed on 5-11-2021) is withdrawn in light of the amendment thereto.
The rejection of claims 1-3, 5-7, 9-11, 13-14 and 16 under 35 U.S.C. 103 as being unpatentable over Altintas et al. (WO 2018/011421 – IDS filed on 5-11-2021) and Ellmark et al. (WO 2016/023960) is withdrawn in light of the amendment thereto.
Claim Rejections Maintained
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
The provisional rejection of claims 1-3, 5-7, 9-11 and 14 on the ground of nonstatutory double patenting as being unpatentable over claims 9-16 and 19-21 of copending Application No. 17/922,781 (reference application) is maintained for reasons of record. The Examiner notes Applicant requests this rejection be held in abeyance until patentable subject matter is identified.
As outlined previously, although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are drawn to conjugates comprising: i) at least one first specific binding molecule which binds CD40, wherein said first specific binding molecule is an agonist of CD40; and ii) at least one second specific binding molecule which binds a tag moiety, wherein said tag moiety is not a cancer antigen, wherein said first specific binding molecule and second specific binding molecule are antigen- binding proteins comprising an antigen-binding domain of an antibody and are covalently linked.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
The rejection of claims 1-3, 5-7, 9-11 and 14 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 is maintained for reasons of record. Cancellation of claims 13 and 16 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 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.
Applicant argues:
1. Table 1shows bispecific conjugates according to the presently claimed invention in form of bispecific antibodies, and specifies the different parts of the bispecific antibody: the first binding molecule being the anti-CD40 IgG (and subclass thereof); the second specific binding molecule with binds the tag moiety being the scFv indicated in the table; as well as the scFv appending position (in other words, the location on the parental antibody to which the scFv is attached by means of a linker). Thus, the Table present 9 different conjugates according to the present invention and one bispecific conjugate, wherein the scFv is an anti-FITC scFv. Not only are these bispecific conjugates described, they were also evaluated experimentally as summarized below. Thus, the Applicant indeed presents conjugates according to the present invention, which show the immunological effect of the present invention as demonstrated by the Example13
2. Figures 6A-C (pasted below) schematically illustrates an example of conjugate according to claim 1.
3. The Example section of the present application presents data provides a reduction to practice and shows the technical effect of the present invention both in vitro and in vivo.
4. The Examiner's contention that antibodies must be defined by their complete sequence of the light and heavy chains (not only the CDR-regions) is not consistent with current knowledge as humanization methods have been routine for decades and as evidenced by the Chen et al. and Burks et al. references “even if one had no guidance as to which amino acids could be substituted, on could still make amino acid substitutions (even in the CDRs) with the expectation that the antibody would still work as expected.”.
Applicant’s arguments have been fully considered and deemed non-persuasive.
With regard to Points 1-3, as set forth supra, the MPEP in 2163 states: “An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function.”
The examiner has identified a lack of art-recognized correlation between the function and the structure responsible for the function with respect to the claimed invention. Both the prior art, and the courts have acknowledged that antibody structure/function relationships are quite complex, and are not merely related to the primary amino acid sequence of the antibody. Both the prior art and the courts have concluded that empirical testing is required to ensure the predicted function of the antibody actually exists in the physical molecule. Moreover, the elements pointed out in Applicant’s arguments (Fig 4, pages 15-17 of the response) as to what conjugates were produced and tested for specific activity. The Examiner notes that no structure-function relationship is defined for the specific binding activities and agonist activity required for the disclosed conjugates (let alone for the scope of the binding molecules embraced by pending claims). Moreover, the specification and drawings were thoroughly considered with respect to what was described and with respect to the antibodies considered to be possessed at the time of filing. Figure 4 is a cartoon depicting the desired conjugate overall bispecific form, but lacks any specificity as to which specific portions of each element are required to maintain the affinity or activity of the disclosed conjugates. Applicant is reminded that the disclosure of how the conjugates were made does not provide specificity as to what sequences, residues, motifs, or portions of the said conjugates are required or what can be altered (and how) and still retain the required activities. Likewise, the disclosure of testing whether the conjugates carry out agonistic activities, such as activation of T-cells, does not provide information as to what elements of the conjugate itself are required. The specification discloses the testing of a multitude of tag peptides to find suitable targets, of which 5 were ultimately identified but does not provide information as to what elements of the conjugate itself are required to bind that tag, as the target can comprise any 5 amino acids of SEQ ID NO 6 or 10-14.
The examples disclose studies demonstrating T cell activation after therapeutic administration with the conjugate Bi-10, does not identify the structural elements of Bi-10 which are required to maintain that activity (Example 2); studies on the agonistic effect of the conjugates on CD40 expression, showing antibodies of the IgG2 subtype are superior to those of the IgG1 subtype (Example 5) do not provide proper description for the claimed genus as the claimed conjugates are not limited to the IgG2 subtype.
Moreover, the examples demonstrating the plasma stability of a peptide upon binding the bispecific conjugates does not describe what aspects of the conjugate confer that stability or what elements are not required for said activity.
Applicant’s arguments that binding molecules which bind CD40 are well known, or that some binding affinity might be predicted in limited examples are not persuasive as the claims are not limited to known binding molecules that bind CD40. The critical aspects of the conjugates themselves that are necessary and sufficient to identify conjugates having the required binding activities set forth in the claims are not described by the specification. Beyond the antibodies disclosed in the listed table, the disclosure lacks the information that would have “permitted the ordinary artisan to immediately envisage the claimed product arising from the disclosed process.” (See, e.g., Fujikawa v. Wattanasin).
As previously noted, MPEP 2163 states:
“Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. 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).”
The claim to a conjugate, defined only by its binding functions, and a description that the first and second specific binding molecules are “antigen binding proteins containing an antigen-binding domain of an antibody and are covalently linked” does not provide adequate structural information of the conjugate itself. While some antibodies which bind one or more elements described as targets in claim 1 may be known in the prior art, the claims are not limited to these known elements, nor do they describe the full genus of any polypeptide or protein or macromolecule which may bind CD40 and have agonist activity, or bind one of the listed tag targets. Moreover, claim 1 does not require that the conjugate itself is bivalent (see claim 2), which was shown in applicant’s disclosure and arguments to be a requirement for certain aspects of its activity in T-cell activation. Additionally claim 1 does not denote where the two binding molecules are covalently linked, thus applicant’s indication of the overall structure of Figure 4 is not commensurate with the claims’ scope. Additionally, claim 1 does not require any particular Ig, or Fc, or other framework for either of the binding molecules, whereas Applicant’s arguments suggest that IgG2 frameworks were more successful for certain activities and an scFv framework was successful for others.
The term “antigen binding domain” is not a term that has universally acknowledged structure in the art, as evidenced by multiple prior art citations in the rejection. The prior art has shown that the precise elements which make up an “antigen-binding domain of an antibody” vary widely, depending on the framework of the antibody, the CDRs, and any added or conjugated elements, such as a second, separate binding domain. The prior art has shown that binding affinity exhibited by an antibody is not predictable based on structure or sequence of the antibody, or even the combination of both antibody sequence and structure. As such, the claims as written do not find adequate written description in the disclosure as filed.
With regard to Point 4, while humanization methods have been routine for decades, they have in ways been perfected. As clearly set forth in the Winters and Harris reference (Immunology Today Vol. 14, No. 6, pages 243-246 that when humanizing a murine antibody one needs to consider the interactions between the framework regions and the CDR loops. Moreover, all “humanized antibodies” had to be empirically tested for specificity ad affinity. Additionally, the reference by Moon et al. (Molecules and Cells Vol. 39 No. 3, pages 217-228) 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.”. Bendig (Methods: A Companion to Methods in Enzymology 8, pages 83-93) clearly demonstrates the unpredictability of altering antibody sequences as she 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 aforementioned references, all of Bendig’s humanized antibodies had to be empirically tested for specificity and affinity. Moreover, Sir Gregory Paul Winter’s Amici Brief to the U.S. Supreme court in the Amgen v. Sanofi case, clearly supports the Examiner’s position as he writes “Amgen’s expert further agreeing that even if antibody sequences were “similar”, the 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. Finally, the art cited by the Examiner clearly demonstrated that the framework regions play an important role in antigen binding and affinity. As set forth in the rejection, 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, 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).
As outlined previously, the instant claims are drawn to conjugates comprising i) at least one first specific binding molecule which binds CD40, wherein said first specific binding molecule is an agonist of CD40; and ii) at least one second specific binding molecule which binds a tag moiety, wherein said tag moiety is a peptide that comprises at least 5 amino acids of SEQ ID NO:6 or 10-14 and isn’t a cancer antigen, wherein said first specific binding molecule and second specific binding molecule are antigen- binding proteins comprising an antigen-binding domain of an antibody and are covalently linked wherein:
The first specific binding molecule: (i) further comprises a Fc region of an antibody; and/or (ii) is bivalent; and/or (iii) is a monoclonal antibody; and/or (iv) is a F(ab')2 fragment of a monoclonal antibody; and/or (v) binds human CD40, and is an agonist of human CD40 (claim 2);
the first specific binding molecule is an antibody of the IgG isotype (claim 3);
the first specific binding molecule is an antibody selected from: CP-870,893, APX005M, ADC-1013, ChiLob 7/4, SEA-CD40 and ABS-1150/1151, or an antibody comprising the antigen-binding domain of any one of said antibodies (claim 5);
the second specific binding molecule is an scFv (claim 6);
the first specific binding molecule and the second specific binding molecule are both human or humanized (claim 7);
the conjugate comprises one first specific binding molecule, which is an antibody, and two second specific binding molecules, which are scFvs, and: i) one scFv is conjugated to the CH3 domain of each heavy chain of said antibody; or ii) one scFv is conjugated to the CL domain of each light chain of said antibody (claim 9);
the tag moiety comprises no human B-cell epitopes (claim 10);
the tag moiety comprises a B-cell epitopes (claim 11);
the tag moiety is peptide that comprises an artificial or non- native amino acid sequence, or consists of an amino acid sequence not found in a mammalian protein (claim 14); and
Consequently, the instant claims encompass an incalculable number of combinations of binding molecules.
As pointed out by Applicant, the specification is limited to the disclosure of 9 different conjugate binding molecules, and one bispecific conjugate binding molecule as provided in table 1.
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While the listed conjugates may have had empirical testing with respect to their target binding activities, no structural aspects of these conjugates are directly linked to those activities or functions. There is no common core structure, sequence or motif in the conjugate (i.e. the antibodies themselves) which is required to perform the functions of a) bind CD40 and have agonist activity and b) bind the family of tag molecules now recited in the claims. It is the conjugates themselves that must meet the written description requirement.
Consequently, the claims describing the conjugated antibodies do not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph since the specification is silent as to what particular immunoepitopes and specific framework regions are required for a given antibody to have the required functions [to bind to CD40 and to bind a given tag moiety (e.g. MTTE – SEQ ID NO:6), or fragments thereof (at least 5 amino acids of 6, or 10-14)] especially when incorporated into a multivalent construct (antibody).
Even with the amendment identifying certain sequences for the tag moiety as the target of the second specific binding molecule, this fails to provide any structural information as to what the overall second specific binding molecule sequence or structure itself could be. Identification of a binding molecule of an antigen binding domain based solely on the sequence of the target is highly unpredictable in the art of immunology, and the specification fails to provide any structural/functional relationship with respect to the nature of the specific binding molecules which make up the claimed conjugate.
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 binding molecules (antibodies), Applicant must adequately describe which combination of variable regions and framework (Fd) regions that 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 binding molecules (antibodies) to which the claims are drawn, such as a correlation between the structure of the antibody and its recited function (specific antibody binding), so that the skilled artisan could immediately envision, or recognize at least a substantial number of members of the claimed genus of multivalent conjugates. The specification fails to disclose what combination of variable regions and Fd regions are essential for antibody binding, or which amino acids might be added, replaced or deleted so that the resultant domain peptide retains the binding specificity of its parent, or by which other amino acids the essential amino acids might be replaced so that the resultant peptide retains the binding specificity of its parent. Therefore, the specification fails to adequately describe at least a substantial number of members of the genus of antibodies to which the claims refer; and accordingly, the specification fails to adequately describe at least a substantial number of members of the claimed genus of multivalent conjugates.
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). Skolnick notes that sequence-to function methods can be powerful in limited situations, but the art has determined significant limitations in their application, and suggests that these methods will increasingly fail as protein-sequence databases grow in size and diversity and concludes “Inaccurate use of sequence-to-function methods has led to significant function-annotation errors in the sequence databases.” (see page p34). 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) because any given protein may have several biochemical functions. “Knowing the protein structure by itself is insufficient to annotate a number of functional classes and is also insufficient for annotating the specific details of protein function.” (see Box 2). Skolnick discloses the difficulty with proteins which have similar folding patterns and sequences, but differing functions, providing a number of examples including immunoglobulin (antibody) type molecules. “Each superfamily is further composed of protein families and each individual family can have radically different functions.” (see 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]). Caldas et al. discusses the difficulty in retaining affinity for a target in CDR replacement (see pages 947-948), noting that a multiplicity of strategies have been employed in the attempt to transfer CDR’s to new frameworks, and retain target affinity, with varying success. A multiplicity of factors in both the Fd and the CDR influence target affinity that go well beyond simple structural or sequence similarity. “This loss [in affinity] is enhanced as the similarity of the chosen framework and the donor variable regions decreases” which Caldas notes as the “framework effect.” (see page 947). 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. Casadevall et al. describe a study where two monoclonal antibodies of different isotypes (IgG1 and IgA, and all the fragments of the antigen binding regions), all with identical variable regions, binding the same epitope were found to manifest differences in affinity (see page 12272, col 2).
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).
These issues have been acknowledged by the courts. 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 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, none of the conjugates of the rejected claims meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
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).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ROBERT A ZEMAN/Primary Examiner, Art Unit 1645 May 17, 2025
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