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 .
Application Status
In response to Non-Final Office Action mailed on 07/10/2025, applicants' response, arguments and amendments filed on dated 12/08/2025 is acknowledged; in said response applicants’ have amended claims 1 and 6 and canceled claims 3-5, 7 and 9-10. Thus, amended claims 1-2, 6, 8 and 11-12 are pending and elected Group I, Claims 1-2, 6, 8 and 11-12 and as species CH/CL crossover reading on the elected invention is now under consideration for examination.
Withdrawn-Claim Rejections: 35 USC § 103
Previous rejection of claims 1-12 rejected under 35 U.S.C. 103 as being unpatentable over Bruenker et al. (WO 2015/052230 A1; reference provided in the parent application 16/560,375 Office-action) or Klein1et al., (WO 2009/080252) and further in view of Klein2 et al., (MABS., 2016, Vol. 8(6): 1010-1020), is being withdrawn due to claim amendments.
New-Claim Objections
Necessitated by claim amendments
Claim 1 (claims 2, 6, 8 and 11-12 depending therefrom) are objected to for the following informality: Recitation of “and/or” in claim 1, makes the claim indefinite, as it is not clear what limitations must be present. Correction and clarification is required. Examiner suggests amending the claim to recite “…or …” and for examination purposes the claims 2 and 9 are interpreted as “…or…”.
New-Claim Rejections: 35 USC § 112(b)
Necessitated by claim amendments
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.
I. Claim 1 (claims 2, 6, 8 and 11-12 depending therefrom) 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 indefinite in the recitation of “… wherein the first of the two further expression vectors comprises a nucleic acid sequence encoding the light chain and a heavy chain with the T366S, L368A and Y407V mutations in the CH3 domain, and the second of the two further expression vectors comprises a nucleic acid encoding a domain-exchanged light chain and a heavy chain with T366W mutation in the CH3 domain…” for the following reasons. The reference to specific amino acid residues is unclear and confusing in the absence of the specific sequence structure. It is suggested that if the sequences of light and heavy chain and mutants are disclosed in the sequence listing, the corresponding sequence identifier (i.e., SEQ ID NO: X; SEQ ID NO: Y) be used in the claim. Correction and clarification is required.
II. Claim 1 (claims 2, 6, 8 and 11-12 depending therefrom) are rejected under 35 U.S.C. 112, second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 1 is 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; recitation of “and/or” in claim 1 makes the claim indefinite, as it is not clear what limitations must be present. The metes and bounds of claims 1-2, 6, 8 and 11-12 is not clear and thus, it would not be possible to one of ordinary skill in the art to define the metes and bounds of the desired patent protection. The rejection may be overcome by amending the claims to recite “… or …”. Correction and clarification is required. Examiner suggests amending the claim to recite “…or …”.
III. Claim 12 is 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.
The phrase “… with low/reduced product-related impurities”, is considered to be a relative term which renders the claim 12 indefinite, and the specification does not provide a standard for ascertaining the requisite degree i.e., any metric compared to any other process?, and one of ordinary skill in the art would not reasonably determine the claimed “… with low/reduced product-related impurities”, and varies widely depending on the individual situation as well as the person making the determination and is dependent upon set of conditions defined by the individual situation. It is not clear to the examiner as to what are the metrics for “… with low/reduced product-related impurities”, of interest and degree of change in process as compared to any other process is encompassed in the above phrase. Thus, the scope of the claims is unclear. A perusal of the specification does not provide any support and does not recite the specific conditions/metric/changes in the claimed process of interest as compared to any metric and to any other process?, the applicants' intend to encompass. Clarification and correction is required.
Maintained-Claim Rejections: 35 USC § 112(a)
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
Claims 1-2, 6, 8 and 11-12 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 claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The claims require a method for producing a multispecific antibody, which comprises at least three different polypeptides, comprising cultivating a mammalian cell in a cultivation medium, whereby the mammalian cell has been generated by a) transfecting a mammalian cell with a first expression vector and one, two or three further expression vectors, wherein the first expression vector comprises exactly one nucleic acid sequence encoding a polypeptide of the multispecific antibody, and the one, two or three further expression vectors each comprise at least two nucleic acid sequences each encoding different polypeptide chains of the multispecific antibody, wherein the exactly one nucleic acid sequence of the first expression vector is a nucleic acid sequence encoding a light chain polypeptide of the multispecific antibody, … wherein the first of the two further expression vectors comprises a nucleic acid sequence encoding the light chain and a heavy chain with the T366S, L368A and Y407V mutations in the CH3 domain, and the second of the two further expression vectors comprises a nucleic acid encoding a domain-exchanged light chain and a heavy chain with T366W mutation in the CH3 domain… (no specific structure for light and heavy chain of undefined and unlimited structures) b) recovering the multispecific antibody from the cell or the cultivation medium, thereby producing the multispecific antibody; …and wherein in the additional Fab fragment the following modifications were performed: the variable domains VL and VH are replaced by each other, and/or the constant domains CL and CH1 are replaced by each other, wherein i) the first antigen is Abeta and the second antigen is the transferrin receptor, or ii) the first antigen is CD20 and the second antigen is the transferrin receptor (no specific structure of undefined and unlimited structures for epitopes for Abeta, transferrin receptor or CD20 and no specific variable chain sequences for VL, VH, CL and CH1 domains of undefined and unlimited structures; also see claims objections and 35 U.S.C. 112(b) rejection above for claims interpretation).
To provide evidence of possession of a 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. Applicants are directed to MPEP § 2163 for guidelines on compliance with the written description requirement.
The specification provides 4 examples, characterization of bispecific antibodies with specific defined structures i.e., structural information of encoding polynucleotides and their production (see e.g. Example 1 and pp.49, 54, 60 and 63). The specification does not describe the structure of the full genus of multispecific antibodies to be produced. The specification fails to describe the full genus of expression vectors/nucleic acid sequences encompassed in the instant method claims.
The Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) 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, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently recited antibodies to be produced in the instant method can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1; reference provided in the parent application 16/560,375 Office-action. Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of multispecific antibodies to produced, including the encompassed polypeptides and the expression vectors/nucleic acid sequences used in the instant claims.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Abbvie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (759 F.3d 1285 (Fed. Cir. 2014). “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
Consequently, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus of antibodies nor guidance as to which of the myriad of molecules encompassed by the claimed antibodies would meet the limitations of the claims. Further, given the well-known high level of polymorphism of immunoglobulins and antibodies, the skilled artisan would not have recognized that applicant was in possession of the vast repertoire of antibodies encompassed by the claimed invention.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991), 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 [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
The skilled artisan cannot envision the detailed chemical structures of the molecules to be used in the instant method claims, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of identification.
Maintained-Scope of Enablement
Claims 1-2, 6, 8 and 11-12 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 and provides 4 examples, characterization of bispecific antibodies with specific defined structures i.e., structural information of encoding polynucleotides and their production (see e.g. Example 1 and pp.49, 54, 60 and 63), does not reasonably provide enablement for all of the embodiments embraced by the claims i.e., a method for producing a multispecific antibody, which comprises at least three different polypeptides, comprising cultivating a mammalian cell in a cultivation medium, whereby the mammalian cell has been generated by a) transfecting a mammalian cell with a first expression vector and one, two or three further expression vectors, wherein the first expression vector comprises exactly one nucleic acid sequence encoding a polypeptide of the multispecific antibody, and the one, two or three further expression vectors each comprise at least two nucleic acid sequences each encoding different polypeptide chains of the multispecific antibody, wherein the exactly one nucleic acid sequence of the first expression vector is a nucleic acid sequence encoding a light chain polypeptide of the multispecific antibody, … wherein the first of the two further expression vectors comprises a nucleic acid sequence encoding the light chain and a heavy chain with the T366S, L368A and Y407V mutations in the CH3 domain, and the second of the two further expression vectors comprises a nucleic acid encoding a domain-exchanged light chain and a heavy chain with T366W mutation in the CH3 domain… (no specific structure for light and heavy chain of undefined and unlimited structures) b) recovering the multispecific antibody from the cell or the cultivation medium, thereby producing the multispecific antibody; …and wherein in the additional Fab fragment the following modifications were performed: the variable domains VL and VH are replaced by each other, and/or the constant domains CL and CH1 are replaced by each other, wherein i) the first antigen is Abeta and the second antigen is the transferrin receptor, or ii) the first antigen is CD20 and the second antigen is the transferrin receptor (no specific structure of undefined and unlimited structures for epitopes for Abeta, transferrin receptor or CD20 and no specific variable chain sequences for VL, VH, CL and CH1 domains of undefined and unlimited structures; also see claims objections and 35 U.S.C. 112(b) rejection above for claims interpretation). 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 or use the invention commensurate in scope with these claims.
In In re Wands, 8USPQ2d, 1400 (CAFC 1988) page 1404, the factors to be considered in determining whether a disclosure would require undue experimentation 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 claims are broadly drawn to a method for producing a method for producing a multispecific antibody, which comprises at least three different polypeptides, comprising cultivating a mammalian cell in a cultivation medium, whereby the mammalian cell has been generated by a) transfecting a mammalian cell with a first expression vector and one, two or three further expression vectors, wherein the first expression vector comprises exactly one nucleic acid sequence encoding a polypeptide of the multispecific antibody, and the one, two or three further expression vectors each comprise at least two nucleic acid sequences each encoding different polypeptide chains of the multispecific antibody, wherein the exactly one nucleic acid sequence of the first expression vector is a nucleic acid sequence encoding a light chain polypeptide of the multispecific antibody, … wherein the first of the two further expression vectors comprises a nucleic acid sequence encoding the light chain and a heavy chain with the T366S, L368A and Y407V mutations in the CH3 domain, and the second of the two further expression vectors comprises a nucleic acid encoding a domain-exchanged light chain and a heavy chain with T366W mutation in the CH3 domain… (no specific structure for light and heavy chain of undefined and unlimited structures) b) recovering the multispecific antibody from the cell or the cultivation medium, thereby producing the multispecific antibody; …and wherein in the additional Fab fragment the following modifications were performed: the variable domains VL and VH are replaced by each other, and/or the constant domains CL and CH1 are replaced by each other, wherein i) the first antigen is Abeta and the second antigen is the transferrin receptor, or ii) the first antigen is CD20 and the second antigen is the transferrin receptor (no specific structure of undefined and unlimited structures for epitopes for Abeta, transferrin receptor or CD20 and no specific variable chain sequences for VL, VH, CL and CH1 domains of undefined and unlimited structures; also see claims objections and 35 U.S.C. 112(b) rejection above for claims interpretation).
The specification only teaches 4 examples, characterization of bispecific antibodies with specific defined structures i.e., structural information of encoding polynucleotides and their production (see e.g. Example 1 and pp.49, 54, 60 and 63). The specification does not teach a method for producing a multispecific antibody, which comprises at least three different polypeptides, comprising cultivating a mammalian cell in a cultivation medium, whereby the mammalian cell has been generated by a) transfecting a mammalian cell with a first expression vector and one, two or three further expression vectors, wherein the first expression vector comprises exactly one nucleic acid sequence encoding a polypeptide of the multispecific antibody, and the one, two or three further expression vectors each comprise at least two nucleic acid sequences each encoding different polypeptide chains of the multispecific antibody, wherein the exactly one nucleic acid sequence of the first expression vector is a nucleic acid sequence encoding a light chain polypeptide of the multispecific antibody, b) recovering the multispecific antibody from the cell or the cultivation medium, thereby producing the multispecific antibody, nor are there any working examples of such. Thus, the scope of the claims is extremely broad compared to the guidance and exemplification provided in the specification. The scope of the claims must bear a reasonable correlation with the scope of enablement. See In re Fisher, 166 USPQ 19 24 (CCPA 1970).
The nature of the invention is engineered antibodies where the relative level of skill of those in the art is deemed to be high. 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 routinely 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, William E., Fundamental Immunology, 3rd Edition, Raven Press, New York, 1993, Chapter 9, pp. 292-295), under the heading “Fv Structure and Diversity in Three Dimensions”). 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).
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(6):1979-1983). 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. Colman P. M. (Research in Immunology, 1994, Vol. 145:33-36) teaches that even a very conservative substitution may abolish binding or may have very little effect on the binding affinity (see pg. 35, top of left column and pg. 33, right column).
Thus, the state of the art recognized that it would be highly unpredictable that a specific binding member comprising any antibody variable region with undefined structure and with a desired specificity would retain the antigen-binding function. One of ordinary skill in the art could not predictably extrapolate the teachings in the specification to those with one or more substitutions in one or more CDRs i.e., any antibody variable region with undefined structure and with a desired specificity.
In summary, in view of the lack of the predictability of the art to which the invention pertains as evidenced by Paul W. E. and Rudikoff et al. and Colman P. M., the lack of guidance and direction provided by applicant, and the absence of working examples, the Examiner concludes that undue experimentation would be required to practice the invention as claimed.
Applicants’ have traversed the above written-description and enablement with the following arguments: (see pages 5-6 of Applicants’ REMARKS dated 12/08/2025).
Applicants’ argue: “…claim 1 has been amended to recite further structural information, including "wherein the first of the two further expressions vectors comprises a nucleic acid sequence encoding the light chain and a heavy chain with the T366S, L368A and Y407V mutations in the CH3 domain, and the second of the two further expression vectors comprises a nucleic acid encoding a domain- exchanged light chain and a heavy chain with T366W mutation in the CH3 domain" and "wherein the multispecific antibody is a trivalent, bispecific antibody comprising a) two light chains and two heavy chains of an antibody, which specifically binds to a first antigen (and comprises two Fab fragments), b) one additional Fab fragment of an antibody, which specifically binds to a second antigen, wherein said additional Fab fragment is fused via a peptidic linker to the C-terminus of one of the heavy chains of a), and wherein in the additional Fab fragment the following modifications were performed: the variable domains VL and VH are replaced by each other, and/or the constant domains CL and CH1 are replaced by each other, wherein i) the first antigen is Abeta and the second antigen is the transferrin receptor, or ii) the first antigen is CD20 and the second antigen is the transferrin receptor."
The method of claim 1 is now limited to production of an antibody with three expression vectors. the Examiner's attention is drawn to paragraphs [0346] to [0364] which describe production of bispecific, trivalent anti-Human CD20/Human Transferrin Receptor antibodies, and the tables on pages 17, 18 and 19 of the specification which provide data of antibody yield from different methods of production. Paragraphs [0328] to [0345] which describe production of bispecific, trivalent anti-Human A-Beta/Human Transferrin Receptor antibodies, and the tables on pages 15 and 16 of the specification which provide data of antibody yield from different methods of production.
Reply: Applicants' arguments have been considered but are found to be non-persuasive for the following reasons. Examiner continues to maintain the rejection for reasons stated on record (dated 07/10/2025) and additionally for the following reasons. Contrary to applicants’ arguments claims as amended recite certain amino acid residues, remainder of the structure is undefined; no specific structure for light and heavy chain of undefined and unlimited structures and no specific structure of undefined and unlimited structures for epitopes for Abeta, transferrin receptor or CD20 and no specific variable chain sequences for VL, VH, CL and CH1 domains of undefined and unlimited structures; also see claims objections and 35 U.S.C. 112(b) rejection above for claims interpretation.
Examiner continues to maintain the rejection for reasons stated on record, supporting evidence and arguments presented above in maintaining the written-description rejection and enablement rejection. For the above cited reasons, examiner is maintaining the written-description and enablement rejection for claims 1-2, 6, 8 and 11-12.
New-Claim Rejections: 35 USC § 103
Necessitated by claim amendments
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claims 1-2, 6, 8 and 11-12 are rejected under 35 U.S.C. 103(a) as being unpatentable over Imhof-Jung et al., (US 2017/0349669 A1; priority 07/29/2014) and further in view Kannan et al., (US 8,592,562 B2) and Dennis et al., (US 9,611,323 B2).
Regarding claims 1-2, 6, 8 and 11-12, the disclosure of Imhof-Jung et al., (US 2017/0349669 A1; priority 07/29/2014) teaches method for producing a multispecific antibody, wherein the domain exchange is a CH1-CL crossover or a VH-VL-crossover (Abstract; Figs. 1a-1p; 2: Claims; and entire document); which comprises at least three different polypeptides (¶ [0079-0080]), comprising the following steps: cultivating a transfected CHO mammalian cell in a cultivation medium, whereby the transfected CHO mammalian cell has been generated by a) co-transfecting a CHO mammalian cell with a first expression vector and one, two or three two further expression vectors (¶ [0374], [0080]), wherein the transfected CHO mammalian cell stably expresses the multispecific antibody (¶ [0115-0118]), wherein the first expression vector comprises exactly one nucleic acid sequence encoding a polypeptide of the multispecific antibody, and the one, two or three two further expression vectors each comprise at least two nucleic acid sequences each encoding different polypeptide chains of the multispecific antibody (¶ [0080], [0118], [0374]), wherein the first of the two further expression vectors comprises a nucleic acid sequence encoding the light chain and a heavy chain with the T366S, L368A and Y407V mutations in the CH3 domain, and the second of the two further expression vectors comprises a nucleic acid encoding a domain-exchanged light chain and a heavy chain with T366W mutation in the CH3 domain (¶ [0683]; and entire document); wherein two of the polypeptide chains of the multispecific antibody comprise a domain exchange (¶ [0672], [0683-0684); wherein the multispecific antibody is a trivalent, bispecific antibody, comprising a) a first light chain and a first heavy chain of a full length antibody which specifically binds to a first antigen, b) a second heavy chain of a full length antibody which when paired with the first light chain, specifically binds to the first antigen, and c) a Fab fragment, which specifically binds to a second antigen, fused via a peptidic linker to the C-terminus of one of the heavy chains of a) or b), wherein the constant domains CL and CH1 of the second light chain and the second heavy chain are replaced by each other (¶ [0194]); wherein the method is for producing a multispecific antibody preparation with low/reduced product-related impurities (¶ [0041]).
Examiner below has reproduced the relevant sections form Imhof-Jung et al., (US 2017/0349669 A1; priority 07/29/2014):
[0041] According to the invention the formation of undesired side products during the production of the multispecific antibodies can be reduced due to the introduction of oppositely charged amino acids at specific positions in the CH1 and CL domains.
[0078] “Multispecific antibodies” bind two or more different epitopes (for example, two, three, four, or more different epitopes). The epitopes may be on the same or different antigens. An example of a multispecific antibody is a “bispecific antibody” which binds two different epitopes.
[0079] When an antibody possesses more than one specificity, the recognized epitopes may be associated with a single antigen or with more than one antigen.
[0080] The term “valent” as used herein denotes the presence of a specified number of binding sites in an antibody molecule. A natural antibody for example has two binding sites and is bivalent. As such, the term “trivalent” denotes the presence of three binding sites in an antibody molecule.
[0194] In one embodiment of the invention the modified heavy chain of a multispecific antibody according to the invention consists of a sequential arrangement (N-terminal to C-terminal direction) of the VL and CL domains of the second light chain (however particular amino acid substitutions in said VL and CL domains as described for the invention are possible). Thus, in this embodiment the multispecific antibody comprises at least two Fab fragments, including a first Fab fragment derived from said first antibody (non-crossed Fab fragment) and a second Fab fragment derived from said second antibody (crossed Fab fragment), wherein the multispecific antibody according to this embodiment does not comprise the respective Fc domains of said first and said second antibody (hence, the multispecific antibody is devoid of an Fc domain). In one embodiment, a multispecific antibody comprises two to five Fab fragments. In one embodiment of a multispecific antibody the Fab fragments are connected with each other via a peptide linker. The term “peptide linker” as used herein denotes a peptide with amino acid sequences, which is preferably of synthetic origin. In one embodiment a peptide linker is used to connect one of the Fab fragments to the C- or N-terminus of the other Fab fragment in order to form a multispecific antibody according to the invention. In one preferred embodiment said peptide linker is a peptide with an amino acid sequence with a length of at least 5 amino acids, in one embodiment with a length of 5 to 100, in a further embodiment of 10 to 50 amino acids. In one embodiment said peptide linker is (GxS).sub.n or (GxS).sub.n G.sub.m with G=glycine, S=serine, and (x=3, n=3, 4, 5 or 6, and m=0, 1, 2 or 3) or (x=4, n=2, 3, 4 or 5 and m=0, 1, 2 or 3), in one embodiment x=4 and n=2 or 3, in a further embodiment x=4 and n=2. In one embodiment said peptide linker is (G.sub.4S).sub.2. The peptide linker is used to connect the first and the second Fab fragment. In one embodiment the first Fab fragment is connected to the C- or N-terminus of the second Fab fragment. An exemplary scheme of a multispecific antibody of this embodiment, which is devoid of an Fc domain, is depicted in FIG. 2 (upper field). The multispecific antibody according to FIG. 2 (upper field) is herein also referred to as “Fab-CrossFab”. Multispecific antibodies of this format have been previously described in WO 2013/026835.
[0374] Another object of the invention is a host cell comprising a nucleic acid according to the invention. Another object of the invention is a host cell comprising an expression vector according to the invention. In one embodiment the host cell is a HEK293 cells or a CHO cell.
[0672] This section describes the characterization of the multispecific antibodies with VL-VH/CL-CH1 domain exchange (CrossMAb.sup.Fab) with emphasis on their correct assembly. The expected primary structures were analyzed by electrospray ionization mass spectrometry (ESI-MS) of the deglycosylated intact CrossMAbs and in special cases of the deglycosylated/limited LysC digested CrossMabs.
[0683] For all constructs knob-into-hole heterodimerization technology was used with a typical knob (T366W) substitution in the first CH3 domain and the corresponding hole substitutions (T366S, L368A and Y407V) in the second CH3 domain (as well as two additional introduced cysteine residues S354C/Y349′C) (contained in the respective corresponding heavy chain (HC) sequences depicted above).
[0684] Purification and Characterization of Bivalent, Bispecific Antibodies which Bind to ANG2 and VEGF, with VL-VH/CL-CH1 Domain Exchange (CrossMAbFab) in One Binding Arm and with Two Charged Amino Acid Substitutions in the CH1/CL Interface.
However, Imhof-Jung et al., are silent regarding wherein the expression vectors are used at a plasmid ratio of 1 (first expression vector) to 1 (first further expression vector) to 3 (second further expression vector) (as in claim 1); and wherein i) the first antigen is Abeta and the second antigen is the transferrin receptor, or ii) (as in claim 1).
Regarding claim 1, Kannan et al., (US 8,592,562 B2) provide teaching, suggestion and motivation for wherein the expression vectors are used at a plasmid ratio of 1 (first expression vector) to 1 (first further expression vector) to 3 (second further expression vector) and optimization of expression vector plasmids during transfection to obtain desired multispecific antibody comprising the desired molar ratio of heavy and light chains i.e., “methods include culturing a host cell comprising nucleic acids encoding the first and second CH3-containing polypeptides such that the polypeptides are co-expressed by the cell. In certain embodiments, the nucleic acids encoding the first and the second CH3-containing polypeptides are provided to the host cell at a ratio, for example 1:1, 1:2, 2:1, 1:3, 3:1, 1:4, 4:1, 1:5, 5:1, 1:6, 6:1, 1:7, 7:1, 1:8, 8:1, 1:9, 9:1, 1:10, 10:1. It is contemplated that altering the ratio of nucleic acids may increase the production of heterodimeric molecules versus homodimeric molecule” (see Col. 3, lines 23-32; and Col. 4, lines 28-31).
Examiner below has reproduced the relevant sections form Kannan et al., (US 8,592,562 B2):
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Regarding claim 1, Dennis et al., (US 9,611,323 B2) provide teaching, suggestion and motivation for the choice of i) the first antigen is Abeta and the second antigen is the transferrin receptor depending on the experimental need (see Abstract; Col. 16, lines 23-30; and entire document).
Examiner below has reproduced the relevant sections form Dennis et al., (US 9,611,323 B2):
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As such, disclosure of strategy and methods for optimization of expression vector plasmids during transfection to obtain desired multispecific antibody comprising the desired molar ratio of heavy and light chains and altering the ratio of nucleic acids may increase the production of heterodimeric molecules versus homodimeric molecule and to generate multispecific antibody comprising the first antigen is Abeta and the second antigen is the transferrin receptor depending on the experimental need (as in claim 1) such as that of references of Kannan et al., and Dennis et al., teaching the advantages of said modifications in the claimed method, clearly suggests to a skilled artisan to modify the teachings of Imhof-Jung et al., and incorporate the structural and functional elements of Kannan et al., and Dennis et al., in the claimed method for producing a multispecific antibody of interest including the structural and functional elements of the instant invention are well known in the art (for details see the rejection above).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the claimed method of industrial significance and incorporate the modification to the claimed method, as suggested Kannan et al., and Dennis et al., and to modify the teachings of Imhof-Jung et al. A person of ordinary skill in the art is motivated to make such change, because to include optimization of expression vector plasmids during transfection to obtain desired multispecific antibody comprising the desired molar ratio of heavy and light chains and altering the ratio of nucleic acids may increase the production of heterodimeric molecules versus homodimeric molecule and to generate multispecific antibody comprising the first antigen is Abeta and the second antigen is the transferrin receptor depending on the experimental need and a skilled artisan would realize such a modification would be useful to increase the product recovery and to produce multispecific antibody of interest with good yield with low/reduced product-related impurities and comprising the first antigen is Abeta and the second antigen is the transferrin receptor depending on the experimental need. One of ordinary skill in the art has a reasonable expectation of success at adding the step i.e., to include optimization of expression vector plasmids during transfection to obtain desired multispecific antibody comprising the desired molar ratio of heavy and light chains and altering the ratio of nucleic acids may increase the production of heterodimeric molecules versus homodimeric molecule and to generate multispecific antibody comprising the first antigen is Abeta and the second antigen is the transferrin receptor depending on the experimental need as suggested in the teachings Kannan et al., and Dennis et al., and are well known in the art. Therefore, the inventions as a whole lack an inventive step over the prior art. The expectation of success is high, because the combined teachings of Imhof-Jung et al., Kannan et al., and Dennis et al., also provide the structural and functional elements of the instant invention (Teaching, Suggestion and Motivation).
Regarding specific choice of plasmid ratio are also provided/suggested in the combination of references, and examiner also takes the position the following position; optimization of known variables, and the examiner finds support in: MPEP 2144.05 [R-5]: A. Optimization Within Prior Art Conditions or Through Routine Experimentation Generally, differences in choice of ratio of plasmids etc., will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation". As to optimization results, a patent will not be granted based upon the optimization of result effective variables when the optimization is obtained through routine experimentation unless there is a showing of unexpected results which properly rebuts the prima facie case of obviousness. See In re Boesch, 617 F.2d 272,276,205 USPQ 215,219 (CCPA 1980). See also In re Woodruff, 919 F.2d 1575, 1578, 16 USPQ2d 1934, 1936-37 (Fed. Cir. 1990), and In re Aller, 220 F2d 454,456,105 USPQ 233,235 (CCPA 1955). Furthermore, "it is prima facie obvious to combine two compositions or two methods each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition or third method to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Given this extensive teaching in prior art (Imhof-Jung et al., Kannan et al., and Dennis et al.,) i.e., a method for producing a multispecific antibody, which comprises at least three different polypeptides, comprising cultivating a mammalian cell in a cultivation medium, whereby the mammalian cell has been generated by a) transfecting a mammalian cell with a first expression vector and one, two or three further expression vectors, wherein the first expression vector comprises exactly one nucleic acid sequence encoding a polypeptide of the multispecific antibody, and the one, two or three further expression vectors each comprise at least two nucleic acid sequences each encoding different polypeptide chains of the multispecific antibody, wherein the exactly one nucleic acid sequence of the first expression vector is a nucleic acid sequence encoding a light chain polypeptide of the multispecific antibody, … wherein the first of the two further expression vectors comprises a nucleic acid sequence encoding the light chain and a heavy chain with the T366S, L368A and Y407V mutations in the CH3 domain, and the second of the two further expression vectors comprises a nucleic acid encoding a domain-exchanged light chain and a heavy chain with T366W mutation in the CH3 domain… (no specific structure for light and heavy chain of undefined and unlimited structures) b) recovering the multispecific antibody from the cell or the cultivation medium, thereby producing the multispecific antibody; …and wherein in the additional Fab fragment the following modifications were performed: the variable domains VL and VH are replaced by each other, and/or the constant domains CL and CH1 are replaced by each other, wherein i) the first antigen is Abeta and the second antigen is the transferrin receptor, or ii) the first antigen is CD20 and the second antigen is the transferrin receptor (no specific structure of undefined and unlimited structures for epitopes for Abeta, transferrin receptor or CD20 and no specific variable chain sequences for VL, VH, CL and CH1 domains of undefined and unlimited structures, as taught by the instant invention and as claimed in claims 1-2, 6, 8 and 11-12 is not of innovation but of ordinary skill in the art and the expectation of success is extremely high i.e., “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.”KSR, 550 U.S. at, 82 USPQ2d at 1397”.
Hence, claims 1-2, 6, 8 and 11-12 are rejected under 35 U.S.C. 103(a) as being unpatentable over Imhof-Jung et al., (US 2017/0349669 A1; priority 07/29/2014) and further in view Kannan et al., (US 8,592,562 B2) and Dennis et al., (US 9,611,323 B2).
Applicants’ have traversed the above 35 U.S.C. 103(a) rejection following claim amendments and said arguments are relevant to the new rejection (see page 6 of Applicants’ REMARKS dated 12/08/2025).
Applicants’ argue: “…claim 1 has been amended to include the limitation "wherein the expression vectors are used at a plasmid ratio of 1 (first expression vector) to 1 (first further expression vector) to 3 (second further expression vector)." Neither Bruenker, Klein1 nor Klein2 recite using expression vectors at a plasmid ratio of 1:1:3. Thus claim 1 is not obvious over”.
Reply: Applicants’ arguments have been fully considered but are not deemed persuasive for the following reasons. Contrary to applicants’ arguments and assertions, examiner has provided new references that do indeed teach and suggest the structural and functional elements of the instant invention (for details see the rejection above). Therefore, examiner continues to take the position that each and every element of the instant invention is taught in the combination of cited references and that the combined teachings in the cited prior art provides a reasonable expectation of success and predictability for claimed method.
Examiner has provided arguments above and it is obvious to follow the teaching, suggestion or motivation in the prior art. To reject a claim based on this rationale, Office personnel must resolve the Graham factual inquiries. Then, Office personnel must articulate the following:
(1) a finding that there was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings;
(2) a finding that there was reasonable expectation of success; and
(3) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness. MPEP 2143(I)(G).
All of the above elements are directly discussed in the body of the rejection. Regarding element (2), the reasonable expectation of success Kannan et al., (US 8,592,562 B2) provide teaching, suggestion and motivation for wherein the expression vectors are used at a plasmid ratio of 1 (first expression vector) to 1 (first further expression vector) to 3 (second further expression vector) and optimization of expression vector plasmids during transfection to obtain desired multispecific antibody comprising the desired molar ratio of heavy and light chains i.e., “methods include culturing a host cell comprising nucleic acids encoding the first and second CH3-containing polypeptides such that the polypeptides are co-expressed by the cell. In certain embodiments, the nucleic acids encoding the first and the second CH3-containing polypeptides are provided to the host cell at a ratio, for example 1:1, 1:2, 2:1, 1:3, 3:1, 1:4, 4:1, 1:5, 5:1, 1:6, 6:1, 1:7, 7:1, 1:8, 8:1, 1:9, 9:1, 1:10, 10:1. It is contemplated that altering the ratio of nucleic acids may increase the production of heterodimeric molecules versus homodimeric molecule” (see Col. 3, lines 23-32; and Col. 4, lines 28-31).
The Supreme Court has acknowledged: When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation...103 likely bars its patentability...if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person's skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions ...... the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) (emphasis added).
Examiner continues to hold the position that the cited references render claims 1-2, 6, 8 and 11-12 prima facie obvious to one of ordinary skill in the art when one applies the Teaching, Suggestion and Motivation (TSM) test under the rationale for arriving at a conclusion of obviousness as suggested by the KSR ruling. The rationale applied for this rejection is as follows:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) “Obvious to try”–choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
The combined teachings in the cited prior art provides a reasonable expectation of success and predictability for the claimed invention. In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Summary of Pending Issues
The following is a summary of issues pending in the instant application.
Claim 1 (claims 2, 6, 8 and 11-12 depending therefrom) are objected for informality.
Claim 1 (claims 2, 6, 8 and 11-12 depending therefrom) are rejected under 35 U.S.C. 112(b).
Claims 1-2, 6, 8 and 11-12 are rejected under 35 U.S.C. 112(a) for written-description and enablement.
Claims 1-2, 6, 8 and 11-12 are rejected under 35 U.S.C. 103(a) as being unpatentable over Imhof-Jung et al., (US 2017/0349669 A1; priority 07/29/2014) and further in view Kannan et al., (US 8,592,562 B2) and Dennis et al., (US 9,611,323 B2).
Conclusion
None of the claims are allowable. Claims 1-2, 6, 8 and 11-12 are objected/rejected for the reasons identified in the Rejections and Summary sections of this Office Action. Applicants’ must respond to the rejections in each of the sections in this Office Action to be fully responsive for prosecution.
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 extension fee 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.
Regarding filing an After Final amendment, Applicants are directed to MPEP 714.13, which states:
II. ENTRY NOT A MATTER OF RIGHT
It should be kept in mind that applicant cannot, as a matter of right, amend any finally rejected claims, add new claims after a final rejection (see 37 CFR 1.116) or reinstate previously canceled claims. Except where an amendment merely cancels claims, adopts examiner suggestions, removes issues for appeal, or in some other way requires ONLY A CURSORY REVIEW by the examiner (e.g., typographical errors), compliance with the requirement of a showing under 37 CFR 1.116(b)(3) is expected in all amendments after final rejection. An affidavit or other evidence filed after a final rejection, but before or on the same date of filing an appeal, may be entered upon a showing of good and sufficient reasons why the affidavit or other evidence is necessary and was not earlier presented in compliance with 37 CFR 1.116(e). See 37 CFR 41.33 and MPEP § 1206 for information on affidavit or other evidence filed after appeal. (Examiner's emphasis) If more than a cursory review is required, Applicants are referred to CFR §1.114.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GANAPATHIRAMA RAGHU whose telephone number is (571)272-4533. The examiner can normally be reached on M-F 8:30am-5pm EST.
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/GANAPATHIRAMA RAGHU/ Primary Examiner, Art Unit 1652