DETAILED ACTION
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 .
Election/Restriction:
2. Applicant's election without traverse of species of antibody: in the CDRH2 region:
(i) The substitution of S49 by another amino acid selected from A or G,
(ii) The substitution of T52 by another amino acid selected from A, N or S; and
in the CDRH3 region:
(i) The substitution of V95 by another amino acid selected from A, S or T,
(ii) The substitution of S96 by another amino acid selected from A, G, H, K, N, R or T, filed on 6/11/2026 is acknowledged.
Amended claims 1, 9, (6/25/2026), and previously presented claims 2-8, 10-12, 14, are under consideration by the Examiner.
Claims 13, 16-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claim 15 has been canceled.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on 6/16/2022 is in compliance with the provisions of 37 CFR 1.97 and has been considered by the examiner.
Applicant is reminded of their duty to disclose to the Office all information known to the person to be material to patentability as defined in 37 CFR 1.56. As stated therein, “[e]ach individual associated with the filing and prosecution of a patent application has a duty of candor and good faith in dealing with the Office, which includes a duty to disclose to the Office all information known to that individual to be material to patentability as defined in this section”.
Claim Rejections - 35 USC § 112(a), written description
4. 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.
4a. Claims 1-12, 14, are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant has claimed a variant of a therapeutic anti-TNF alpha antibody comprising variable domains VH and VL of sequences SEQ ID NO: 1 and SEQ ID NO: 2, said variant comprising at least two amino acid substitutions in at least one sequence overlapping one of the CDRH2 or CDRH3 regions determining the complementarity of said VH variable domain;
where said at least two amino acid substitutions in the sequence overlapping the CDRH2 region are: (i) the substitution of S49 by another amino acid selected from A or G. wherein S49 is located at position 49 in SEQ ID NO: 1; (ii)the substitution of T52 by another amino acid selected from A, N or S, wherein T52 is located at position 52 in SEQ ID NO: 1;
wherein said at least two amino acid substitutions in the sequence overlapping the CDRH3 region are selected from the group consisting of: (i) the substitution of V95 by another amino acid selected from A, S or T, wherein V95 is located at position 99 in SEQ ID NO: 1; and
(ii) the substitution of S96 by another amino acid selected from A, G, H, K, N, Q, R or T, wherein S96 is located at position 100 in SEQ ID NO: 1;
with the exclusion of variants comprising the residues V89 or L89, V95, K96, Y97, L98, P99 and S100; V89, V95, A96, Y97, L98, P99 and S100; wherein said variant presenting a reduced immunogenic potential and a TNF alpha binding affinity at least equal or superior, compared to the therapeutic anti-TNF alpha antibody from which it is derived, however Applicant has not provided description of a single variable domain antibody with mixing and matching of the CDRH2 and CDRH3 regions with the different substitutions.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. § 112(a), "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by 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 genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3).
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), the following is noted.
To show invention, a patentee must convey in its disclosure that it “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358).
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted: “A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers. 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002).
As discussed above, Applicant has claimed variants of a therapeutic anti-TNF alpha antibody comprising variable domains VH and VL of sequences SEQ ID NO: 1 and SEQ ID NO: 2, said variant comprising at least two amino acid substitutions in at least one sequence overlapping one of the CDRH2 or CDRH3 regions determining the complementarity of said VH variable domain, however Applicant has not provided written description for which variants of anti-TNF alpha antibody would possess the desirable features recited in the claims.
Recent court cases have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See for example AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) as well as Amgen v. Sanofi. (Fed Cir, 2017-1480. 10/5/2017). Indeed, in Amgen the court indicates that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e. the antigen, as knowledge of the chemical structure of an antigen does not give the required kind of structure-identifying information about the corresponding antibodies, with the antibody-antigen relationship be analogized as a search for a key on a ring with a million keys on it.
Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361).
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
In the instant case, the specification discloses specific CDRH2 mutants set forth in Table 3, page 39, and specific CDRH3 mutants set forth in Table 4, page 41. Applicant has not disclosed the various mixing and matching of CDRH2 and CDRH3 mutants as recited in the claims. Applicant is reminded that the courts have long ruled that “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. 358 F.3d at 927, 69 USPQ2d at 1895. As such, disclosure of a screening assay to test for functional properties of an antibody does not provide evidence of possession of the antibody itself.
It is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, CDR2 and CDR3, which provide the majority of the contact residues for the binding of the antibody to its target epitope.
The amino acid sequences and conformations of the heavy chain CDRs are critical in maintaining the antigen binding specificity and affinity. It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al., 1982, see entire document, particularly the abstract and the middle of the left column of page 1982). However, as discussed above, only the specific mutations in Tables 3 and 4, pages 39, and 41, respectively, [0119] and [0122], respectively, have been described.
Indeed, in AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) the court ruled that all of the antibodies disclosed by AbbVie were all structurally similar as they were variants of a starting antibody named Joe9 and therefore did not serve to inform artisans as to the breadth of structures which had the recited function of cytokine binding. In the instant application, the instant claims recite variants of anti-TNF alpha antibodies while the specification does not disclose structures which necessarily have the requisite functions. The instant specification fails to disclose sufficient structural information to indicate to artisans that Applicant had possession of the various antibodies as presently claimed. Therefore, it appears that the broad genus of antibodies recited in Applicant’s claims lacks adequate written description because there does not appear to be sufficient correlation between the structure of the antibodies in question and their recited functional activities. As such a skilled artisan would reasonably conclude that Applicant was not in possession of the recited genus of antibodies. Therefore, there is insufficient written description for genus of antigen-binding immunoglobulin molecules having the claimed “limitations” at the time the invention was made and as disclosed in the specification as filed under the written description provision of 35 USC 112.
Appellant has been reminded that Vas-Cath makes clear that the written description provision of 35 USC 112 is severable from its enablement provision (See page 1115).
Claim Rejections - 35 USC § 112(a), scope of enablement
4b. Claims 1-12, and 14 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 variant of a therapeutic anti-TNF alpha antibody comprising a light chain of sequence SEQ ID NO: 2 or 32 and a heavy chain of sequence SEQ ID NO: 24 to 31, does not reasonably provide enablement for an antibody as recited in claim 1. 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.
Instant claim 1 encompasses anti-TNF alpha antibody variants with at least two amino acid substitutions in each of the CDRH2 and the CDRH3 regions. Thus, these claims encompass variant antibodies, while the specification only discloses a variant of a therapeutic anti-TNF alpha antibody comprising a light chain of sequence SEQ ID NO: 2 or 32 and a heavy chain of sequence SEQ ID NO: 24 to 31.
Claim 1 recites “a variant of a therapeutic anti-TNF alpha antibody comprising variable domains VH and VL of sequences SEQ ID NO: 1 and SEQ ID NO: 2, said variant comprising at least two amino acid substitutions in at least one sequence overlapping one of the CDRH2 or CDRH3 regions determining the complementarity of said VH variable domain;
where said at least two amino acid substitutions in the sequence overlapping the CDRH2 region are selected from the group consisting of:
- the substitution of S49 by another amino acid selected from A or G. wherein S49 is located at position 49 in SEQ ID NO: 1;
- the substitution of A50 by another amino acid selected from G, 5, T or D, wherein A50 is located at position 50 in SEQ ID NO: 1;
- the substitution of T52 by another amino acid selected from A, N or S. wherein T52 is located at position 52 in SEQ ID NO: 1;
- the substitution S54G. wherein S54 is located at position 55 in SEQ ID NO: 1; and
- the substitution of 157 by another amino acid selected from A, H, N, Q, R, 5, T or WL wherein 157 is located at position 58 in SEQ ID NO: 1; and when the variant comprises the residue A49 then it also comprises the residue N52, 552 or 552 and the residue G54;
wherein said at least two amino acid substitutions in the sequence overlapping the CDRH3 region are selected from the group consisting of:
- the substitution of V89 by L. wherein V89 is located at position 93 in SEQ ID NO: 1;
- the substitution of V95 by another amino acid selected from A, S or T. wherein V95 is located at position 99 in SEQ ID NO: 1;
- the substitution of 596 by another amino acid selected from A, G, H, K, N, Q, R or TL wherein 596 is located at position 100 in SEQ ID NO: 1;
- the substitution of Y97 by H. wherein Y97 is located at position 101 in SEQ ID NO: 1;
- the substitution of L98 by T, wherein L98 is located at position 102 in SEQ ID NO: 1;
- the substitution of 599 by P, wherein 599 is located at position 103 in SEQ ID NO: 1; and
- the substitution of T100 by another amino acid selected from P or S, wherein T100 is located at position 104 in SEQ ID NO: 1;
with the exclusion of variants comprising the residues V89 or L89, V95, K96, Y97, L98, P99 and S100; V89, V95, A96, Y97, L98, P99 and S100; wherein said variant presenting a reduced immunogenic potential and a TNF alpha binding affinity at least equal or superior, compared to the therapeutic anti-TNF alpha antibody from which it is derived.”
There is insufficient guidance and direction as to make and use all the encompassed anti-TNF alpha antibodies that are encompassed by the scope of the claim. The genus encompasses variant anti-TNF alpha antibodies, that comprise disparate amino acid sequences, including numerous differences in linear and conformational epitopes. The specification does not provide sufficient guidance as to which of the amino acid substitutions in the CDRH3 region, for example, would retain structural or functional activity and specificity of the antibody. For example, Lederman et al. disclose that a single amino acid substitution in a common allele ablates binding of a monoclonal antibody (See abstract). Li et al. also disclose that dissociation of immunoreactivity from other biological activities when constructing analogs (See entire document). Because of this lack of guidance, the extended experimentation that would be required to determine which modifications would be acceptable to retain structural and functional activity, and the fact that the relationship between the sequence of a protein/peptide and its tertiary structure (i.e. its activity) are not well understood and are not predictable it would require an undue amount of experimentation for one of skill in the art to arrive at the claimed invention. Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112(a), have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states on page 1404:
"Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. The nature of the invention is a method of using engineered antibodies and immunotherapy where the relative level of skill of those in the art is deemed to be high. In view of the lack of the predictability of the art to which the invention pertains as evidenced by the Lederman et al and Li et al references, the lack of guidance and direction provided by applicant, and the absence of working examples, undue experimentation would be required to make and use the claimed antibodies with no reasonable expectation of success, commensurate in scope with the claimed invention.
The claims are overly broad because no guidance is provided as to which of the myriad of antibodies encompassed by the claims will retain the characteristics of the desired antibody. No actual or prophetic examples on expected performance parameters for the possible variants of the claimed anti-TNF alpha antibody molecule have been disclosed except for an antibody comprising a light chain of sequence SEQ ID NO: 2 or 32 and a heavy chain of sequence SEQ ID NO: 24 to 31. Furthermore, it is known in the art that even single amino acid changes or differences in the amino acid sequence of a protein can have dramatic effects on the protein's function.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. 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 parent 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. 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 (Proc. Natl. Acad. Sci. USA 1982 Vol 79 page 1979). 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. It is unlikely that an antibody as defined by the claims which may contain less than the full complement of CDRs from the heavy chain variable regions of the anti-TNF alpha antibody in unspecified order have the required binding function. The specification provides no direction or guidance regarding how to produce antibodies as broadly defined by the claims. Undue experimentation would be required to produce the invention commensurate with the scope of the claims from the written disclosure alone.
As evidenced by Adair et al. (US Patent 6,632,927) transfer of CDR regions alone are often not sufficient to provide satisfactory binding activity in the CDR-grafted product (col.2 lines 58-61). Panka et al (Proc. Natl. Acad. Sci. USA Vol 85, 3080-3084, 5/88) demonstrate that a single amino acid substitution of serine for alanine results in decreased affinity. In at least one case it is well known that an amino acid residue in the framework region is involved in antigen binding (Amit et al, Science Vol 233, 747-753, 1986). One of skill in the art would neither expect nor predict the appropriate functioning of the antibody as broadly as is claimed. It is suggested that the specific CDR regions of the heavy chain region of the anti-TNF alpha antibody be explicitly recited within the claim. Therefore, in view of the lack of guidance in the specification and in view of the discussion above one of skill in the art would be required to perform undue experimentation in order to make and use the claimed invention.
Applicant has claimed a genus of anti-TNF alpha antibodies which are required to have specific CDRH2 and CDRH3 sequences recited by SEQ ID NO. The only reasonable way to make an antibody that is guaranteed to have a specific sequence or sequences are required by the instant claims, is to use the techniques of recombinant molecular biology. It is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR 1,2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. 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 parent immunoglobulin (Janeway et al., see entire selection). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al., see entire document, particularly the abstract and the middle of the left column of page 1982).
As stated above the antibody sequences which are not fixed by the instant claim language can be effectively random and thus there does not appear to be any predictability as to which sequences will or will not maintain antigen binding activity except for those which have six fully defined non-degenerate CDR sequences, three in the VH and three in the VL. Thus, there is no disclosed data which would reasonably allow artisans to make the full breadth of what is encompassed by the instant claim language.
Therefore, in view of the breadth of the instant claimed invention, the guidance and direction of the instant specification and the teachings of the art, artisans would be unable to make and use the full breadth of Applicant’s genus of anti-TNF alpha antibodies, as presently claimed without first performing extensive unpredictable basic research and experimentation.
Claim Rejections - 35 USC § 112(b)
5. 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.
5a. Claims 1-12, and 14 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 pre-AIA the applicant regards as the invention.
Claim 1 is rejected as vague and indefinite for several reasons.
Claim 1, line 6, is vague and indefinite because it recites “overlapping the CDRH2 region” which is confusing. It is suggested that the claim be amended to recite “in the CDRH2 region” for clarity.
Similarly, claim 1, line 17, is vague and indefinite because it recites “overlapping the CDRH3 region” which is confusing. It is suggested that the claim be amended to recite “in the CDRH2 region” for clarity.
Claim 1, lines 2-3, is vague and indefinite because it recites “…comprising at least two amino acid substitutions in at least one sequence overlapping one of the CDRH2 or CDRH3 regions” which is confusing. It is suggested that the claim be amended to recite the specific amino acid substitutions for clarity.
Similarly, claims 2-8 are rejected as vague and indefinite for the recitation of “overlapping the…. region” for the reasons set forth above with respect to independent claim 1.
Claim 1, lines 29-30, is vague and indefinite because it recites “with the exclusion of variants comprising the residues V89 or L89, V95, K96, Y97, L98, P99 and S100; V89, V95, A96, Y97, L98, P99 and S100;” which is confusing because it is unclear where these variants are located in SEQ ID NO:1.
Claim 1, lines 31-32, is rejected as vague and indefinite for the recitation of “reduced immunogenic potential and a TNF alpha binding affinity at least equal or superior” which limitations are subjective. Furthermore, the term “potential” is itself vague and indefinite. It is suggested that the claim be amended to recite the specific numerical limitations for which there is a basis in the instant specification.
Claim 1, line 33, is rejected as vague and indefinite for the recitation of “…from which it is derived”. Firstly, it is unclear what variant “it” refers to. Secondly the limitation “derived” is also vague and indefinite because it is unclear how the variant is “derived” from the parent therapeutic anti-TNF alpha antibody. This limitation encompasses the parent therapeutic anti-TNF alpha antibody but not the resulting variant.
Similarly claim 11 is rejected as vague and indefinite for the recitation of “…derived”.
Claim 2, line 2, is rejected as an improper Markush claim because it recites “selected from” rather than “selected from the group consisting of”.
Similarly, claims 3-5 6, 8, are rejected as improper Markush claims because they recites “selected from” rather than “selected from the group consisting of”.
Claims 10, and 14, are rejected as vague and indefinite insofar as they depend on rejected claim 1 for their limitations.
Conclusion
Claims 1-12, and 14 are rejected.
No claim is allowed.
A variant of a therapeutic anti-TNF alpha antibody comprising a light chain of sequence SEQ ID NO: 2 or 32 and a heavy chain of sequence SEQ ID NO: 24 to 31 is allowable.
Advisory Information
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/PREMA M MERTZ/ Primary Examiner, Art Unit 1674
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