DETAILED ACTION
1. The present application is being examined under the pre-AIA first to invent provisions.
2. Applicant’s election of Group I (drawn to an expression vector and a host cell) and the species of Arg at position 409 and Leu at position 405 in the reply filed on September 18, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-82 and 85 have been canceled.
Claim 104 has been added.
Claims 83, 84, and 86-104 are pending and currently under consideration as they read on the elected invention.
3. 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.
4. Claims 83, 84, and 86-104 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.
A) The claims are indefinite in that they only recite the number of amino acid positions without reciting the numbering system.
There are several numbering systems used when referring to the amino acid positions in the Fc region. For example, Presta (US 6,737,056) teaches that EU and Kabat are two different systems. In Table 6, Presta teaches that position S239 in EU numbering is also referred as position 252 in Kabat. It is suggested that the claims be amended to recite the numbering system used (e.g. EU numbering system if there is support in the instant specification).
Further, the phrase "such as" recited in claim 83 with respect to the dissociation constant renders the claim and the dependent claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
B) The claims are indefinite in the recitation of an expression vector comprising nucleic acid constructs used in a method for producing a heterodimeric protein, said method comprising the recited steps of providing the first nucleic-acid construct and a second nucleic-acid construct, co-expressing the first and second nucleic-acid, and obtaining the heterodimeric protein because the metes and bounds of the claims are unclear. A single claim which claims both a product and a method step of using the product is indefinite. See MPEP 2173.05(p). Here, the claimed limitation of “used in a method for producing a heterodimeric protein, said method comprising the following steps” set forth in steps (a) and (d) is not directed to the expression vector, but rather to actions of providing a first nucleic-acid and a second nucleic acid, co-expressing the nucleic-acids, and obtaining the heterodimeric protein which creates confusion as to when direct infringement occurs.
For examination, the methods steps are read as intended uses of the product—an expression vector.
C) The claims are indefinite in the recitation of “and” followed by and/or” in independent claim 83 when describing the first and the second CH3 regions because the metes and bounds of the claims are ambiguous. It is not clear which element is encompassed by the claims in view of the recitation of and/or.
Further, the claims are indefinite in reciting “when assayed as described in Example 21”. However, it is not cleared if the claims only referred to the assay method described in Example 21 of the Fc variants disclosed. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parteFressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993). See MPEP 2173.05(s)
5. 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.
6. Claims 83, 84, 86-94, and 96-104 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are drawn to an expression vector comprising nucleic acid constructs comprising:
a first nucleic construct encoding a first polypeptide comprising a first CH3 region having an amino acid other than Lys (K), Leu (L), or Met (M) at position 409, and
a second nucleic acid construct encoding a second polypeptide comprising a second CH3 region having an amino acid substitution at position selected from the group consisting of 366, 368, 370, 399, 405, and 407, and/or
wherein the sequences of the first and second CH3 are such that the dissociation constants of homodimeric interactions of each of the CH3 regions are between, e.g. 0.01 and 10 micromolar when assayed as described in Example 21.
The claims exclude the amino acid residues in position 409 in the first CH3 but do not set forth the amino acid residues in position 409. The claims recite the positions in the second CH3 that are substituted but do not set forth the amino acid residues in those positions. Further, in view of the recitation of “and/or”, the claims read on the first CH3 and the second CH3 are defined by their dissociation constants assayed in Example 21 rather than the structure (e.g. specific amino acid substitutions in specific positions in the first CH3 and the second CH3).
The specification discloses structurally defined heterodimeric Fc. For example, the specification discloses K409 can be mutated to specific amino acid residues and showed that majority of the naturally occurring amino acids induces Fab-arm exchange except K409L or K409M (e.g. see Table 1 in pages 69-70 in the instant specification as-filed). The specification further discloses a CH3 Fc variants having specific substitutions in position 409 pair with another CH3 variant having specific substitutions in F405 (e.g. see Example 21 in page 71 of the specification as-filed).
The recitation of the claimed IgG class Fc-region encompassing the functional / structural limitations do not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
While the instant specification does disclose certain modifications replacing the naturally occurring amino acids in specific positions in the CH3 region of the human IgG Fc region with another specific standard proteinogenic amino acids for enhanced heterodimer formation, the claims recite “having an amino acid other than Lys, Leu, or Met at position 409” and having an amino acid substitution at a position selected from the group consisting of 366, 368, 370, 399, 405, and 407” which do not set forth the specific amino acid residues that are used to replace the pre-exiting residues in these positions.
The instant application has not provided a sufficient description showing possession of the necessary 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 of the first CH3 and the second CH3 as recited.
For example, Ng et al. (Anal. Methods, 2023, 15:445-454) teach that there are at least 500 naturally occurring amino acids, of which only 20 standard proteinogenic amino acids are used universally across all organisms in synthesis of peptides and proteins (e.g. see Abstract).
Note that the disclosure of specific amino acid substitutions in specific positions in the CH3 regions of a human IgG Fc region are not sufficient (e.g. not sufficient representing species) to provide written description support for the broad genus currently recited. Merely reproducing a claim limitation in the specification or even pointing to an original claim, does not satisfy the written description requirement, unless the claim itself conveys enough information to show that the inventor has possession of the claimed invention at the time of the filing.
It was well known that minor structural differences even among structurally related CH3 can result in substantially different biological pharmacological activities. For example, Arathoon et al. (US 7,951,917, reference on IDS) teach that making CH3 variants for the purpose of enhancing heterodimerization requires first to identify the residues to be replaced, followed by studying amino acid replacement including examination of the three-dimensional structure of the
interface because mutations (especially combination mutations) can potentially affect antigen-binding characteristics and glycosylation of the heteromultimers formed.
In Novozymes A/S et al. v. Dupont Nutrition Biosciences APS et al., 2013 WL3779376, Case No. 2012-1433, C.A.Fed. (Wis.), the court states:
“The effects of any given mutation or combination of mutations in a variant can differ depending on the position(s) modified and the specific mutation implemented at each position. Some mutations may have no discernible effect on enzyme function, somemay lead to varying degrees of instability or functional impairment, and some may actually improve enzyme activity or impart other desirable properties, such as improved stability at high temperatures.” Page 5.
The instant application disclosed specific substitutions in particular
positions in the Fc regions of an antibody. However, the specification has
not provided a sufficient description showing possession of the necessary functional characteristics coupled with a known or disclosed correlation between functions (e.g. binds FcRn with different affinity than a parent or promoting the formation of a heterodimeric IgG class Fc region) and the structure of the IgG class Fc-region, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus broadly encompassed by the claimed invention.
A skilled artisan cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus that exhibit the functional properties as recited.
It does not appear based upon the disclosure of specific heterodimeric Fc having
specific amino acid substitutions in specific positions alone that 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 limited number of species disclosed and the extensive variation permitted within the genus of the heterodimeric protein encoded by the nucleic acid constructs in an expression vector.
“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.” California v. Eli Lilly and Co. 43 USPQ2d 1398 (Fed. Cir. 1997).
The disclosure must allow one skilled in the art to visualize or recognize
the identity of the subject matter of the claim. Regents of the University of Id. 43 USPQ2d at 1406.
In the absence of disclosure of relevant, identifying characteristics of the heterodimeric protein, there is insufficient written disclosure under 35 U.S.C. 112, first paragraph.
Therefore, there is insufficient written description for genera of the expression vector comprising nucleic acid constructs encoding a first CH3 and a second CH3 broadly encompassed by claims, other than the variants structurally defined by the description in the specification as filed under the written description provision of 35 USC 112, first paragraph.
7. 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.
8. Claims 83, 84, and 86-104 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-36 of US 9,150,663 (the ‘663 Patent).
The instant claims are drawn to an expression vector comprising nucleic acid constructs used in a method for producing a heterodimeric protein said method comprising the steps of providing a first and second nucleic-acid constructs, each encoding a first CH3 and a second CH3, co-expressing said first and second nucleic-acid constructs in a host cell, and obtaining the heterodimeric protein from the cell culture.
The claims in the ‘663 Patent are drawn to an in vitro method for generating a hete3rodimeric antibody comprising the steps of providing the first CH3 and a second CH3, incubating them together, and obtaining the heterodimeric antibody.
Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the claims in the ‘663 Patent are drawn to the same or nearly the same methods encompassing the same or nearly the same method steps to arriving at obtaining the heterodimeric protein via the first and the second CH3 regions having the same or nearly the same amino acid substitutions. While the instant claims are drawn to an expression vector, the intended uses of the vector encompassing the same method steps as recited in the claims in the ‘663 Patent. As such, the claims in the ‘663 Patent would anticipate the instant invention.
The Examiner recognized that there was a Restriction Requirement in USSN 13/642,253 (matured in to the ‘663 Patent) restricting a method of generating heterodimeric proteins away from nucleic acids.
However, the instant claims as written encompass the method steps recited in the claims in the ‘663 Patent. Further, given the ‘663 Patent is followed by a CON relationship for the subsequent application, and in view of Amgen, Inc. v. F. Hoffman-La Roche Ltd., 580 F.3d 1340 (Fed. Cir. 2009) which indicated that the prohibition under 35 U.S.C. 121 does not apply to claims in a pending case which are directed to a non-elected invention of an application and the case is not a divisional of the application, the above obviousness-type double patenting rejection is set forth.
9. No claim is allowed.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHUN W DAHLE/Primary Examiner, Art Unit 1641
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