Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Elections/Restrictions
Applicant's election with traverse of Group I, claims 1-9 and 12 and species: SEQ ID NO: 16, SEQ ID NO: 3, SEQ ID NO: 9, PE38, leukemia, non-Hodgkin’s lymphoma, hairy cell leukemia, and humans in the reply filed 12/12/2025 is acknowledged. The traversal is on the ground(s) that the antibody of Group I is also used in the other, restricted group. This is not found persuasive because the restriction requirement splits up the invention into statutory categories of invention. Group I is drawn to a product, while Group II is drawn to a method of use. As is, these groups are considered patentably distinct until Group I is found allowable, at which point Group II would be rejoined and examined.
The requirement is still deemed proper and is therefore made FINAL.
Claims 11, 13-21 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions and species, there being no allowable generic or linking claims. Election was made in the reply filed 12/12/2025.
Claims 1-9 and 12 are now under consideration in the instant Office Action.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because the instant specification makes reference to drawings, but there are no copies submitted on file. It is unclear what the figures and drawings Applicant is making reference to throughout the application. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 25. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the terms ImMunoGeneTics (page 25), which are trade names or marks used in commerce, have been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 4 is objected to because of the following informalities: the claim currently recites “ alternatively, the second polypeptide chain further comprises a heavy chain constant region CH1, preferably a human heavy chain constant region CH1 fused to the C-terminus of the heavy chain variable region (VH).” It is recommended that Applicant remove the phrase “alternatively” and rewrite the limitations of the claim.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-5 and 12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
With regard to claims 1-3, 5, and 12, the claims are considered indefinite for the recitation of “having at least 75% sequence identity” and “comprises an amino acid sequence as shown in SEQ ID NO” when referring to heavy/light chain variable domain sequences, respectively. More specifically, the claim language “an amino acid sequence” is ambiguous because this claim language indicates any sequence of a recited SEQ ID NO could satisfy the claim limitation, from the full-length sequence to any portion of the sequence (i.e., fragments). As such, it is unclear as to what the scope of the claim is regarding “an amino acid sequence” claim language. This rejection can be obviated by amending the claims to incorporate closed claim language with regard to sequences instead of the “an amino acid sequence” language. For example, closed claim language of “comprising the amino acid sequence of SEQ ID NO” clearly indicates that the full-length of the recited SEQ ID NO is required to meet the claim limitation.
Claim 1 recites “… a polypeptide molecule comprising two polypeptide chains as follows:” The recitation of “as follows” is unclear as it does not properly ascertain what limitations are to be encompassed by the claims. Applicant is encouraged to use language commonly found in patents, such as language like “wherein” to recite the limitations of their claim.
Additionally, regarding claims 2-4, the phrases “preferably” and/or “more preferably” render the claims indefinite because it is unclear whether the limitation(s) following the phrases are part of the claimed invention or not. See MPEP § 2173.05(d). The presence of at least two interpretations renders these claims indefinite.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-9 and 12 are directed to any recombinant immunotoxin that binds to CD22 . As such, the claim is directed to an antibody defined entirely by function (binding). See MPEP §2163(I)(A) which states:
"The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art recognized correlation or relationship between the structure of the invention and its function. A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.”
In this case, antibodies generally share certain characteristics such as Fc regions or hinge regions. However, these structures are not correlated with the binding function of the antibody. The hyper variable regions (HVRs), i.e., complementarity determining regions (CDRs) of an antibody, are well established in the art as the portion of the binding region which imparts the specificity of an antibody. However, there is no way to a priori look at an antigen sequence (CD22) and envisage the combination of six CDRs that will bind that antigen. First, even highly related CDRs may not bind the same target. See for example Kussie (instant PTO-892) who demonstrates that a single amino acid change in the heavy chain of an antibody which binds p-axophenylarsonate (Ars) completely abrogates the ability of the antibody to bind Ars but adds the functionality of binding the structurally related p-azophenylsulfonate (e.g., abstract). Second, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (p.7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on page 11).
Thus, the art recognizes that the CDRs define the binding properties of an antibody and that even single amino acid changes to this region can completely abrogate the binding specificity of an antibody. As a further example, see Chen et al., 1995 (instant PTO-892) which demonstrates single amino acid changes in the VH CDR2 sequence can increase binding, decrease binding, destroy binding, or have no effect on binding when compared to the wild-type antibody.
See also Koenig 2017 (instant PTO-892), which provides a large mutation analysis study where every amino acid in both variable regions are substituted with every other amino acid. Looking at figure 1 of Koenig, the bottom half of each section (labeled VEGF) relates to the ability of the mutant to bind the original target, with blue meaning a reduced affinity and black meaning a complete loss of binding ability. In VH-CDR2, for example, mutating any given residue to cysteine, which is encompassed by the instant claims, resulted in reduced binding at 12 residues and a complete loss of binding at 5 residues. That is, at 100% of the positions, mutation to cysteine reduced or ablated the antibody’s ability to bind the target. Looking at a specific position, in 100% of the mutations of residue 55, binding was reduced (15/19) or eliminated (4/19). While residues 56-65 appear more tolerant of change, residues 50-55 are generally intolerant of change.
It is appreciated that Koenig is studying one specific antibody and there is no evidence that the instant antibodies would react in the same way. However, this is part of the problem. It is entirely unclear from the specification which residues of Applicant’s CDRs are tolerant or intolerant to change, and whether those tolerant positions are only tolerant to conservative mutations. The fact that some residues might tolerate mutation does not convey to the skilled artisan that Applicant knew which of the claimed residues were tolerant of such, i.e., does not convey that Applicant was in possession of those sequences which are mutated yet preserve the claimed function. In other words, the specification fails to convey possession of an invention commensurate in scope with what is now claimed and therefore fails to meet the written description requirement. Looking at Koenig figure 2A, ~200 mutations in the CDR region of the VH chain completely abrogates any binding. While 2B appears to indicate that the CDRs of VL are more tolerant of change than the heavy chain CDRs, still over half of the mutations reduce binding compared to the parent.
Thus, making changes to the CDR sequence of an antibody is a highly unpredictable process and the skilled artisan could not a priori make any predictions regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required functions.
The claims are drawn to a genus of anti-CD22 recombinant immunotoxins, which are polypeptides that comprise a VH and VL, and the VH/VL sequences comprise an amino acid sequence of the recited sequences or an amino acid sequence having at least 75% identity to the recited amino acid sequences SEQ ID NOs: 16, 3, and 9, while the specification provides exemplary antibodies, defined by their full heavy chain and light chain sequences. It is specifically noted that these exemplary antibodies comprise the full-length sequences of VH/VL recited in the instant claims; Applicant discloses three antibody species comprised within the claimed genus of anti-CD22 immunotoxins. However, even though Applicant has disclosed numerous species of anti-CD22 antibodies via their VH/VL sequences, Applicant is claiming a large and structurally diverse genus of anti-CD22 immunotoxins, each of which can comprise one of numerous possible combinations of fragments of the recited VH/VL domains as well as up to 25% modifications of their amino acid sequences.
Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically which combinations of fragments of the recited VH/VL domains yield antibodies that are specific for/capable of binding CD22. Accordingly, Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus, and Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a). The disclosure of these specific antibodies would not convey to the artisan that Applicant was in possession of the full genus of all antibodies which possess the required functions nor does it allow the skilled artisan to envisage the specific structure of such antibodies.
Further note the decision in Amgen v. Sanofi 2017, where the Court supported previous decisions (Centocor 2011; Abbvie 2014) that defining an antibody solely by what it binds does not satisfy the written description requirement, stating that this would allow patentees to “claim antibodies by describing something that is not the invention, i.e., the antigen”. This decision has precipitated guidance to the Office instructing that the portion of MPEP 2163 regarding the “newly characterized antigen test” (indicating a well-characterized antigen is sufficient to satisfy written description for antibodies which bind that antigen) should no longer be used and that contrary materials should not be relied upon as reflecting the current state of the law.
It is appreciated that certain claims do include at least one VH/VL sequence, e.g., claim 3 requires SEQ ID NOs: 16 and 3, but also includes any “homologue” of those sequences, a homologue being defined as noted above to include no particular structure so long as the function is retained. Claim 1 requires both VH/VL chains but, as above, includes variants which have only 75% of the structure defined, the definition including any change to the structure so long as the function is retained.
However, as above, arbitrarily altering any amino acid in the CDR of an antibody is unpredictable and the specification does not convey possession of any CDRs other than those of the disclosed antibodies. Further, it is well-known in the art that specificity of an antibody stems from the interaction of six CDRs. Moreover, CDRs are not generally recognized as interchangeable, such that using one CDR from one antibody would not be reasonably expected to confer the same binding properties or even the same binding target when combined with two to five CDRs from other antibodies. For example, WO 2008068048 (instant PTO-892) discloses an antibody with a heavy chain comprising three CDRs (SEQ ID NO: 2) that binds secreted aspartyl protease from Candida sp. US 20170355756 (instant PTO-892) describes the same three CDRs in the heavy chain (C10-VH3) combined with a different light chain that binds human TDP-43. There is no evidence in the instant specification that a single CDR placed in the context of two to five other CDRS, regardless of what those other CDRs are, would result in the required function, nor that a single chain is correlated to the required function when combined with any other chain. As such, the specification fails to set forth a structure-function correlation sufficient to claim all possible antibodies defined by function and one-three CDRs or alterations thereof.
As such, the disclosure of a few antibody sequences does not convey possession of other antibodies with the same binding properties; possession of the precisely defined sequence of six CDRs is required.
With respect to product claims 1-9 and 12, it is recognized that information which is well known in the art need not be described in detail in the specification (MPEP §2163(II)(A)(2)). See, e.g., Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1379-80, 231 USPQ 81, 90 (Fed. Cir. 1986). However, sufficient information must be provided to show that the inventor had possession of the invention as claimed. MPEP §2163(II)(A)(3)(a) also discusses Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004), where a method of using a PGHS-2 inhibitor did not meet the written description as the inhibitor itself was not sufficiently described, clearly indicating that written description of the compound is still required in a method of using that compound. In this case, it is clear from the specification that the invention is in a new antibody, or at the least disclosure of a new antibody that could not have been envisaged from the prior art indicates that the prior art was not in possession of all “CD22 antibodies” for use in recombinant immunotoxins. Thus, the prior art cannot provide sufficient written description of this genus of compounds and the specification as filed, disclosing one antibody, does not sufficiently describe the genus either as there is an unknown amount of structurally distinct antibodies in this genus (see Amgen and Centocor decisions discussed above).
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Vas-Cath, Inc., v. Mahurkar, 935 F.2d at 1563, 19 U.S.P.Q.2d at 1116. The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function. An antibody described only by functional characteristic, such as antibody that binds CD22 or one of the claimed epitopes, without any known or disclosed correlation between that function and the structure of the sequence, is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. In re Bell, 991 F.2d 781, 26 U.S.P.Q.2d 1529 (Fed. Cir. 1993). In re Deuel, 51 F.3d 1552, 34 U.S.P.Q.2d 1210 (Fed. Cir. 1995). In the instant case, the specification provides insufficient direction or guidance concerning the relationship between the structure of the possible antibody to demonstrate possession of the breadth of the genus of CD22 antibodies encompassed by the instant claims, especially in view of the unpredictability of such an endeavor. The prior art as evidenced by Edwards et al., 2003 (instant PTO-892) teaches there is a substantially huge antibody diversity produced to one single antigen target. Edwards provides evidence that over 1000 antibodies, all different amino acid sequences, were generated towards one single protein antigen target (see abstract). Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Without this guidance or direction the skilled artisan would not consider applicant to be in possession of the claimed genus of antibodies because the skilled artisan recognizes that even seemingly minor changes made without guidance or direction as to the relationship between the particular amino acid sequence of the instantly claimed antibody and its ability to bind antigen, can dramatically affect antigen-antibody binding.
Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genus of an antibody that binds CD22. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester v. G.D. Searle & Co., 358 F.3d 916, 69 USPQ2d 1886 (Fed. Cir. 2004).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
What constitutes a "representative number" is an inverse function of the skill and knowledge in the art. Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements 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.
To provide adequate written description and evidence of possession of the claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In the instant case, the only factors present in the claims are a recitation of one generic, broad genus that encompassed a diverse and huge number of possible antibodies that bind the disclosed epitope. The specification does not provide a consistent structure for all of the possible antibodies and fails to provide a representative number of species for the claimed genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that they invented what is claimed.” (See Vas-Cath at page 1116).
With the exception of specifically disclosed antibodies with specific CDRs, the skilled artisan cannot envision the detailed chemical structure of all of the encompassed antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Therefore, claims 1-9 and 12 do not meet the written description requirement.
Claims 1-9 and 12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a humanized anti-CD22 recombinant immunotoxin comprising complete VH/VL sequences, does not reasonably provide enablement for any anti-CD22 recombinant immunotoxins without fully defined sequences. 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 and use the invention commensurate in scope with these claims.
MPEP § 2164.01 states:
The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term “undue experimentation,” it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include but are not limited to:
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The breadth of the claims;
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The nature of the invention;
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The state of the prior art;
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The level of one of ordinary skill;
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The level of predictability in the art;
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The amount of direction provided by the inventor;
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The existence of working examples; and
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The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors most relevant to this rejection are 1) the breadth of the claims, 2) the state of the prior art, and 3) the amount of direction provided by the inventor. In the instant case, the amount of direction provided by the inventor, the breadth of the claims, and the state of the prior art disclosed in the specification, as filed, would not be sufficient to enable the skilled artisan to make and/or use the claimed invention at the time the application was filed without undue experimentation.
The Breadth of the Claims
The claims as currently written are extremely broad. The instant claims drawn to an isolated anti-CD22 immunotoxin comprising a VH and VL that have an amino acid sequence of the recited SEQ ID NOs (emphasis added). Under the broadest reasonable interpretation, the recitation of “an amino acid sequence” indicates that fragments of the recited VH/VL SEQ ID NOs can satisfy the claim limitations; as such, the sequences recited in claim 1 do not necessarily satisfy the written description requirement. Furthermore, the instant claims recite that the anti-CD22 immunotoxin further comprises heavy and light chain variable domains comprising an amino acid sequence of the recited SEQ ID NOs or an amino acid sequence having at least 75% identity to the recited SEQ ID NOs. Claims 6-8 are drawn to a nucleic acid molecule comprising a nucleotide sequence encoding the anti-CD22 antibody or antigen-binding fragment thereof according to claim 1, a vector comprising said nucleic acid molecule, and a host cell comprising said nucleic acid molecule or said vector; it is not specified that said nucleic acid molecule, vector, and/or host cell is isolated and thus claims 6-8 generally read on a transgene within a transgenic animal.
The State of the Prior Art/Level of Unpredictability in the Art
The state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of antibodies generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, under the heading “Fv Structure and Diversity in Three Dimensions”, in instant PTO-892). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30).
Thus, the state of the art recognized that it would be highly unpredictable that a specific antibody comprising less than all six parental CDRs would have antigen binding function. The minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of a murine or humanized antibody includes six CDRs (three from the heavy chain variable region and three from the light chain variable region) in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function. One of skill in the art would neither expect nor predict the appropriate functioning of the antibody fragments and mutated antibodies of the instant claims as broadly as claimed.
In the case of antibodies, it is especially important to disclose which residues are permissive to mutation. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proceedings of the National Academy of Sciences USA, Vol., 79, Pg. 1979-1983, 1982, in instant PTO-892). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (Abstract).
Not knowing, absent further experimentation, which modifications function and which do not, when, as set forth above, even a single change of an encoded amino acid can unpredictably affect antibody structure and function, leads to one having no predictability or expectation of success for the function of any given antibody modification. Such random experimentation to identify at a later time what structure or fragment or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation.
Moreover, claims not containing elements critical or essential to the practice of the invention, such as antibodies or antibody fragments not having all of the relevant functional complementarity determining regions (CDRs) in the proper site on an appropriate antibody heavy or light chain framework, are not enabled by the disclosure. See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976).
Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
The Amount of Direction Provided by the Inventor/Existence of Working Examples
The instant specification provides exemplary antibodies, defined by their full heavy chain and light chain sequences. It is specifically noted that these exemplary antibodies comprise the full-length sequences of CDRs and VH/VL sequences recites in instant claims 1-3; there are no exemplary antibodies provided that comprise fragments of the recited sequences nor mutations of the recited VH/VL sequences. Based on the language of the instant claims which allows for up to 25% of the amino acid sequences to be modified, the specification does not provide sufficient disclosure for all of the potential combinations that can arise from this scale of modifications that are encompassed within the claim language.
In view of the of the breadth of the claims, the level of predictability in the art to which the invention pertains, as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional antibodies and antigen-binding fragments thereof comprising fewer than the complete VH/VL sequences for the immunotoxin with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively make and practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, commensurate in scope with the claimed invention.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-9 and 12 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Hunter et al. (WO 2014100443 A2, in IDS filed 05/30/2023).
Hunter et al. teaches methods of preparing active immunoconjugates capable of binding to CD22. These immunoconjugates comprise an anti-CD22 antibody, along with a cytotoxic fragment PE38, see paragraph 0085. The anti-CD22 antibody-PE38 conjugate comprises VH/VL sequences, wherein the amino acid sequences of antibodies VL, VH and VH-P38 are respectively SEQ ID NOs: 2-15, 6-11 and 1, see claims 14-24, and sequence listings. After alignment, SEQ ID NOs: 2 and 12-15 respectively have 89% and 87% identity to SEQ ID NO: 16 of the instant application; SEQ ID NOs: 10, 6, 8, 1, and 7 respectively have 92%, 92%, 91%, 90% and 91% identity to SEQ ID NO: 3 of the instant application; SEQ ID NOs: 10, 6, 8, 1, 7, 11 and 9 respectively have 94%, 94%, 93%, 91%, 92%, 91% and 91% identity to SEQ ID NO: 4 of the instant application; and SEQ ID NO: 1 respectively has 96% and 97% identity to SEQ ID NOs: 9 and 10 of the instant application. Hunter et al. also discloses a nucleic acid encoding the conjugate, vector, host cell, drug and composition, wherein the immunoconjugates are linked as antibody-linker-cytotoxin or in the reverse order, see claim 15, and description, paragraphs [0001] - [0004], [0055], [0091] and [0103] - [0107].
Therefore, claims 1-9 and 12 are anticipated by Hunter et al.
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.
Claims 1-9 and 12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-3, 6-10 of copending Application No. 18/246,838, hereinafter ‘838. Although the claims at issue are not identical, they are not patentably distinct from each other.
‘838’s claims are drawn to an isolated anti-CD22 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region (VH) and a light chain variable region (VL) with 6 fully defined CDRs. ‘838’s claim 10 recites an immunoconjugate, wherein said immunoconjugate comprises the same antibody as recited in claim 1. It is specifically noted that instant SEQ ID NOs: 16, 18, 3, and 4 are 100% identical to ‘838’s SEQ ID NOs: 7, 8, 3, and 4, respectively. ‘838 describes further limitations, including VH/VL combinations and how the polypeptide chains are combined/linked, and how the cytotoxin is fused to the VH. ‘838’s specification recites on page 7 that the cytotoxin can be “PE38”. Instant SEQ ID NOs: 9 and 10 comprise 100% matches to ‘838’s SEQ ID NOs: 3 and 4, respectively. ‘838’s claims 6-8 are drawn to a nucleic acid molecule comprising a nucleotide sequence encoding the first and/or second polypeptide chains of the antibody of claim 1 and a vector and a host cell comprising said nucleic acid molecule.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/SELAM BERHANE/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675