Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
The amendment filed July 17, 2026, is acknowledged and has been entered. Claim 132 has been amended.
Claims 1 and 114-132 are pending and are under examination.
Claim Rejections Maintained
Claim Rejections - 35 U.S.C. §§ 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
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.
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
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).
Claims 1 and 114-132 are rejected under 35 U.S.C. 103(a) as being unpatentable over Holliger et al (US 2004/0058400 A1, IDS) in view of Alt et al (FEBS L., 454:90-94, 1999, IDS).
With respect to the claims, Holliger et al teach bispecific and bivalent antibodies (i.e., diabodies) wherein the first polypeptide has the structure of N-(VLA-VHB)-C and the second polypeptide has the structure of N-(VLB-VHA)-C, with a linker between the VL and VH consisting of too few amino acids to allow the VL domain of the polypeptide to combine with the VH domain of the same polypeptide, such that the VHA and VLA pair and the VHB and VLA pair instead would pair and each form a separate epitope binding site functions (see entire document, e.g., pages 3, 8 and 13 and Examples). Holliger et al teach that antibodies comprise hinge cysteines that forms disulfide bonds and that disulfide bonds can be used to crosslink polypeptides to provide stability and making bispecific antibodies with Fc domains by reduction and reoxidation of two antibodies with different specificities (see e.g., pages 7, 8, 11, 12 and 35-38 and Figures).
Holliger et al teach that the constant domains of IgG1 can kill cells by activating complement and that the constant domains of IgG1 bind Fc receptors for other effector functions, while the IgG4 Fc domain limits effector functions (see entire document, e.g., pages 3, 8 and 13 and Examples). Holliger et al further teach that diabodies can be fused to additional proteins or antibody domains, such as a CH3 domain, to increase the size of the diabody for enhanced retention in the serum. Holliger et al teach that the antibodies can bind to HER2, CD3, the hormone drug oestriol, small molecules, CD16 or CD32 (i.e., FcyRI or FcyRll) among other antigens (see pages 4, 9 and 12 and Example 12). Holliger et al teach the antibodies can be humanized (see page 23). Holliger et al teach pharmaceutical compositions comprising such diabodies (see claims). Holliger et al teach that a bispecific antibody targeting HER2 and CD3 can kill cells expressing HER2 and that the bispecific antibody can be used in methods of treating cancer (see e.g., pages 5, 8 and 12).
Holliger et al do not teach linking a hinge linker comprising a cysteine residue (which is disfulide linked to the cysteine in the other protein comprised in the antibody) followed by -CH2-CH3 to antibodies to create multimeric antibodies.
Alt et al teach fusing a CH3 domain or a hinge linker comprising a cysteine residue (which is disfulide linked to the cysteine in the other protein comprised in the antibody) followed by -CH2-CH3, which are from human IgG1, to a single chain diabody or scFv antibody to increase serum half-life (see entire document, e.g., abstract, Figure 1 and pages 90 and 93-94). Alt et al teach that the antibodies can target tumor antigens, bacteria antigens or receptor molecules (see page 90). Alt et al teach that certain therapeutics require Fc effector functions and long serum half-life (see page 90). Alt et al teach introducing a knob-into-hole structure and additional cysteine residues into the CH3 domain to favor formation of heterodimeric heavy chains (see page 93).
Accordingly, it would have been prima facie obvious to make bispecific and bivalent non-human, humanized or human antibodies (i.e., diabodies) wherein the first polypeptide has the structure of N-(VLA-VHB)-C and the second polypeptide has the structure of N-(VLB-VHA)-C, wherein both proteins further comprise a linker with a cysteine residue (which is disulfide linked to the opposite cysteine) and a CH2-CH3 domain from human IgG1 or IgG4 to either the N or C-terminus because adding a linker with a cysteine residue (which is disulfide linked to the opposite cysteine) and a CH2-CH3 domain from human IgG1 or IgG4 would have the advantage of improving half-time of the diabody and have the advantage of increasing stability due to the disulfide bond.
In this case, Alt teach that proteins having a cysteine hinge linker-CH2-CH3 domain can be used to increase serum half-life and Holliger teach adding antibody domains to increase serum half-life, so one of skill in the art would be motivated to use the cysteine linker-CH2-CH3 of human IgG1 or IgG4 at either end of the diabody of Holliger as it would be immediately recognized to be a naturally occurring structure in human serum that would increase half-life, including in antibodies that bind to HER2, bacterial antigens from an infection, CD16 and/or CD32 (while the prior art only mentions CD16 and CD32 and claims 121-124 and 126 recite CD16A, CD16B, CD32A and CD32B, the recitation of CD16 and CD32 would be immediately envisioned to include CD16A, CD16B, CD32A and CD32B as these are the known species of CD16 and CD32 which would be at once envisaged, absent a showing otherwise (see MPEP § 2131.02). As the cysteine linker-CH2-CH3 is larger than a CH3 domain, the size of the diabody would be further increased such that the half-life would have the advantage of being further extended compared to a CH3 only fused construct. Furthermore, depending on the application, the construct would have the added advantage of effector functions when desired (with an IgG1 Fc domain) or limited effector functions (with an IgG4 domain that is considered a variant of IgG1) when not desired and the disulfide-linked cysteine bond would have the advantage of increasing stability of the construct.
Notably, as set forth in the Supreme Court decision in KSR International Co. v. Teleflex Inc. 82 USPQ2d 1385 (2007):
“A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.”KSR, 82 USPQ2d at 1397. “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.”Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR, 82 USPQ2d at 1396. An obviousness determination is not the result of a rigid formula disassociated from the consideration of the facts of a case. Indeed, the common sense of those skilled in the art demonstrates why some combinations would have been obvious where others would not. See KSR Int7 Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) ("The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.").
In this case, based on the knowledge in the antibody art about making bispecific and bivalent antibodies and antibodies in general, it is submitted that a person of ordinary skill in the art using ordinary creativity would have recognized that adding a cysteine linker-CH2-CH3 domain from human IgG1 or IgG4 to each polypeptide of a diabody would have advantages detailed above. Furthermore, such diabodies could target any antigen as claimed as evidenced by Alt and Holliger, such that diabodies targeting antibodies and pharmaceutical compositions comprising such diabodies for use in methods of treating a HER2 expressing cancer and infectious diseases would also be seen as obvious over the references for similar reasons. Then with respect to claim 127, it is noted that Alt et al teach modifying the CH3 domain to create a knob-in-hole structure along with additional cysteine residues to give the advantage of favoring formation of heterodimeric bispecific constructs. Accordingly, a person of ordinary skill in the art using ordinary creativity would have been motivated to modify the CH3 domain to create a knob-in-hole structure in the diabody-Fc construct suggested by the prior art in order to promote proper heterodimeric formation. Notably, as CH2-CH3 domains from each polypeptide dimerize, without a knob-in-hole structure, the CH2-CH3 domains would be more likely to homodimerize than CH2-CH3 domains with a knob-in-hole structure, which would lead to non-functional homodimers being formed. Therefore, modifying CH2-CH3 domains with a knob-in-hole structure would have an advantage in the suggested constructs and these modified IgG1/IgG4 CH2-CH3 domains with a knob-in-hole structure would have at least one amino acid modification as compared to a wild-type Fc domain.
Finally, one of ordinary skill in the art would have a reasonable expectation of success in making such constructs, compositions and using them in methods of treatment as encompassed by the claims as both Alt et al and Holliger et al demonstrate that genetic engineering techniques to join antibody domains using linkers were known in the art and bispecific antibodies had been used to treat diseases in the art.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
In the response, Applicant traverses the rejection.
Applicant submits that:
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1042
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1308
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99
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In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Notably, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In this case, the prior art cited recognized that there is an advantage to increase the size of the recombinant antibody fragment such as a diabody for enhanced retention in the serum and Fc-mediated effector functions when this is desired, such that there were multiple motivations to fuse an IgG1 CH2-CH3 domain to diabodies using a Cys containing linker wherein the first polypeptide has the structure of N-(VLA-VHB)-C and the second polypeptide has the structure of N-(VLB-VHA)-C. Alt specifically states on page 90 that “In lacking the constant regions, recombinant antibody fragments also lack the associated effector functions and are rapidly cleared from serum due to their small size [16]. However, certain therapeutic applications require an IgG molecule with its Fc-mediated effector functions and its long serum half-life” which is clear motivation to add an Cys containing linker Fc to the polypeptides of a diabody and evidence that there was a reasonable expectation of success in making such a construct.
The antibody arts have been studied extensively and one of skill in the art would have recognized that different domains of antibodies are desirable in some situations while not desirable in others, such that they could routinely add or remove domains as needed. The instant claims are broadly drawn to generic diabody molecules comprising a Cys linker, such as a IgG1 hinge and a CH2-CH3 domain and one of skill in the art would recognize that adding an IgG1 hinge-CH2-CH3 domain with knob-in hole mutations to a diabody molecule would have advantages when effector functions were desired and increased serum half-life were desired. In further response to Applicant’s argument, this position is supported throughout many other prior art documents, including Ono et al (JBB, 95(3):231-28, 2003, of record) and Mertens et al (US 2004/0220388 A1, of record). For example, Ono et al teach that adding the Fc of human IgG1 to scFv has the advantage of allowing for more easy purification and longer clearance time in blood and effector functions for use in human therapy (see pages 231-232). Similarly, Mertens et al teach diabodies of the VL-VH form that are bispecific and that by products often need to be removed due to incorrect VL and VH binding which can be minimized with knob in hole mutations using a CH3 domain or an Fc fragment which also has the advantage of increasing molecular weight (see paragraphs 7-8). Then Raubitschek et al (US 6,410,319, of record) teach fusing scFv to hinge-CH2-CH3 and that diabodies can also be used (see columns 14 and 15).
Then with respect to Applicant’s argument that “that the Cys-containing linker recited in the present claims is distinct from a hinge cysteine”, it is noted that the instant claims recite no structure of a Cys-containing linker to distinguish from a cysteine in a hinge, because the hinge region in an antibody is links the Fc region to the rest of the heavy chain, i.e., it is encompassed by the term “linker”, and it comprises a cysteine that forms a disulfide bond. Notably, the instant specification describes linkers comprising cysteines derived from hinge regions and states in ¶ [0034] that “the domains of the first and second polypeptide chain comprising an Fc domain, i.e., optionally, the third and sixth domains, respectively, can further comprise a hinge domain such that the domain comprises a hinge-Fc region”, such that, as currently claimed, a hinge linker is encompassed by the claimed cysteine residue (Cys)-containing linker domain.
With respect to the argument Holliger teaches away from the invention because the inclusion of a CH3 domain decreased the yield of bispecific antibody, it is noted that this instead provides motivation to add a hinge-Fc instead of just a CH3 domain which significantly reduced yield. Furthermore, even if it was expected that a hinge-Fc would also reduce yield, adding the hinge-Fc would be expected to increase serum half-life and add effector function, such that there were clear advantages and reasons to make such a construct even if the yield fell. Notably, when increased serum half-life and effector function is desired, a reduction in yield would not dissuade one from making such a construct because antibody effector function and increase in serum half-life is part of the structure of the Fc domain. Holliger
With respect to the argument that the structures in Alt are completely different from the claimed diabody, it is noted that Alt is being primarily relied upon for its teaching relating to adding Fc domains to recombinant antibody fragments. For example, Alt specifically states that “certain therapeutic applications require an IgG molecule with its Fc-mediated effector functions and its long serum half-life” (see page 90). This teaching applies to recombinant antibody fragments in general and is not limited to the specific antibody structures in Alt.
Accordingly, after careful and complete consideration of Applicant’s response and the record as a whole, for these reasons and the reasons set forth previously, this rejection is maintained.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brad Duffy whose telephone number is (571) 272-9935. The examiner can normally be reached Monday through Friday. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Julie Wu, can be reached at (571) 272-5205. The official fax number for the organization where this application or proceeding is assigned is 571-273-8300.
Respectfully,
Brad Duffy
571-272-9935
/Brad Duffy/
Primary Examiner, Art Unit 1643
September 9, 2026
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