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 .
Claims 1, 6, 20, 22, 25-26 and 29 are pending and being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 62/346,905 filed June 7, 2016 and 62/248,792, filed Oct 30, 2015, is acknowledged.
Rejections Withdrawn
The rejection of claims 1, 6, 20, 22, 25-26 and 29 on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 10,662,254 is withdrawn in view of the terminal disclaimer filed on March 27, 2026.
Claim rejections under - 35 U.S.C. 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 6, 20, 22, 25-26 and 29 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. “Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP § 2163.
The U.S. Court of Appeals for the Federal Circuit recently reaffirmed, in an en banc decision, that the written description requirement for a genus may be satisfied either by (i) the disclosure of a representative number of species falling within the scope of the genus or (ii) structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus. Ariad Pharmaceuticals', Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350, 94 U.S.P.Q.2d 1161, 1171 (en banc) (Fed. Cir. 2010), citing Regents" of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568-69, 43 U.S.P.Q.2d 1398, 1406 (Fed. Cir. 1997) and AbbVie v. Janssen Biotech and Centocor Biologics (Fed. Cir. 2014).
Claim 1 encompass any construct consisting of any isolated IgG1 Fab antibody fragment that terminates with residue D221, according to EU numbering, wherein the IgG1 Fab antibody fragment has reduced or no reactivity towards pre-existing anti-hinge antibodies.
Claim 6 encompasses the construct of claim 1, wherein the IgG1 Fab antibody fragment terminates with amino acids CD.
Claim 20 encompasses the construct of claim 1, wherein the IgG1 Fab antibody fragment comprises a heavy chain constant region that consists of the amino acid sequence set forth in SEQ ID NO: 6 and any conservative modifications thereof.
Claim 22 encompasses a pharmaceutical formulation comprising the construct of claim 1 and a pharmaceutically acceptable carrier.
Claim 25 encompasses a pharmaceutical formulation comprising the construct of claim 6 and a pharmaceutically acceptable carrier.
Claim 26 encompasses a pharmaceutical formulation comprising the construct of claim 20 and a pharmaceutically acceptable carrier.
Claim 29 encompasses any antibody-drug conjugate comprising any construct consisting of any isolated IgG1 Fab antibody fragment that terminates with residue D221 according to EU numbering conjugated to any cytotoxic agent.
The specification discloses therapeutic Fab molecule directed against platelet surface receptor GPIIb/IIIa (abciximab, REOPRO®) is commercially produced by proteolytic cleavage with papain (5), which is the original method of Fab production (6). With the advances in molecular cloning, recombinant expression of antibody fragments has become an attractive route to generate Fab molecules as exemplified by the second approved Fab therapeutic, anti-VEGF (ranibizumab, Lucentis®) (7) and the recently approved Fab against dabigatran (idarucizumab, Praxbind®), see para. [0004]. The C-terminus of an antibody fragment disclosed herein, e.g., a Fab fragment, terminates at amino acid residue D.sub.221 (according to EU numbering), see para. [0065]. One therapeutic Fab molecule directed against platelet surface receptor GPIIb/IIIa (abciximab, REOPRO®) is commercially produced by proteolytic cleavage, see para. [0081].
However, these species fails to convey evidence of possession of the entire genus.
The specification does not describe i. Complete structure, e.g., amino acid sequences of heavy and light chains variable domains, ii. Partial structure, e.g., six CDRs of IgG1 Fab terminates with residue D221 that correlated with binding share by members of the genus as a pharmaceutical composition (claims 22, 25 and 26). Notably, the specification, does not describe the structure, e.g., amino acid sequence of the heavy and light chain variable domains that correlated with binding to all antigens. There are no limitation on the structures or binding function of the Fab fragment for use as a pharmaceutical composition.
It is known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al (J Mol Biol. 334(1): 103-118, 2003; PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla et al (Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Given that hundreds of unique antibody Fab structures may bind a single antigen, the structure of an antibody Fab cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in Abbvie).
Regarding antibody-drug conjugate (claim 29), there are no objective evidences of any antibody-drug conjugate comprising the claimed construct consisting of any IgG1 Fab antibody that terminates with residue D211 according to EU numbering conjugated to any and all cytotoxic agent.
The state of the prior art is such that the location or site of conjugation on the drug and the antibody or Fab fragment affect conjugate stability, and pharmacokinetics of antibody drug conjugates.
For example, Strop et al (Chemistry and Biology 20: 161-167, 2013; PTO 892) teach drug position can have a significant effect on linker stability and antibody pharmacokinetics. The site of conjugation on the drug and antibody can influence ADC properties differently in mice and rats, highlighting potential pitfalls of examining efficacy in mouse xenograft models and toxicity in rats or nonhuman primates, see abstract, p 166, p. 168 right col, in particular.
Nejadmoghaddam (Avicenna Journal of Medical Biotechnology 2(1): 3-23, 2019; PTO 892) discusses major obstacles of antibody-drug conjugates include off-target toxicity, tumor marker selection, antibody specificity, adequately affinity and receptor-mediated internalization are major aspects of choice, cytotoxic payload (e.g., up to 7 drugs per antibody), cytotoxic payload linkage strategy, aqueous solubility, non-immunogenic and stability in storage and bloodstream, see entire document, abstract, p. 15, in particular.
There are no working examples. It is unpredictable which undisclosed IgG1 Fab antibody fragment that terminates with residue D221 is effective as a pharmaceutical composition for treating which disease. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus as broadly claimed.
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), "[claiming antibodies with specific properties, e.g., an antibody that binds to human TNF-a with A2 specificity, can result in a claim that does not meet written description even if the human TNF-a protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
"[A] sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus." Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A "representative number of species" means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780,1790 (Fed. Cir. 2014) ("The '128 and '485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus."). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number" of species.
The "structural features common to the members of the genus" needed for one of skill in the art to 'visualize or recognize' the members of the genus takes into account the state of the art at the time of the invention. For antibodies, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor, 97 USPQ2d at 1875 ("[T]he application only provides amino acid sequence information (a molecular description of the antibody) for a single mouse variable region, i.e., the variable region that the mouse A2 antibody and the chimeric antibody have in common. However, the mouse variable region sequence does not serve as a stepping stone to identifying a human variable region within the scope of the claims."). A chimeric antibody shares the full heavy and light chain variable regions with the corresponding mouse antibody; that is, the structure shared between a mouse and chimeric antibody would generally be expected to conserve the antigen binding activity.
Lastly, possession may not be shown by screening assays. Ariad, 94 USPQ2d at 1167; Centocor at 1876 ("The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.")
An adequate written description must contain enough information about the actual makeup of the claimed products - "a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials", which may be present in "functional terminology when the art has established a correlation between structure and function" (Amgen page 1361).
In Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), the court explained in Amgen that when an antibody is claimed, 35 U.S.C § 112(a) requires adequate written description of the antibody itself. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized" 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 Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear 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).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Therefore, only (1) a construct consisting of an isolated human IgG1 Fab antibody fragment that terminates with residue D211 according to EU numbering, wherein the IgG1 Fab antibody fragment has reduced or no reactivity towards pre-existing human anti-hinge antibodies, (2) Said construct, wherein the IgG1 Fab antibody fragment comprises a heavy chain constant region that consists of the amino acid sequence set forth in SEQ ID NO: 6, (3) a composition comprising said construct and a pharmaceutically acceptable carrier, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Applicant's arguments filed March 27, 2026 have been carefully considered but are not found persuasive.
Applicant’s position is that claim 1 is readily distinguishable from the antibody claims at issue in Amgen. In Amgen, the claims were directed to a genus of monoclonal antibodies defined primarily by their functional ability to bind PCSK9. By contrast, claim 1 of the present application is directed to a construct consisting of an isolated IgG1 Fab antibody fragment defined by specific structural features, irrespective of the antigens to which it can bind.
The present application provides robust support for the claimed structure and its associated advantages. As disclosed in the present application, the claimed IgG1 Fab construct provides significant benefits over conventional IgG formats that are directly attributable to its structural features. As described in paragraph [0005], the upper hinge region of a Fab can be recognized by anti-hinge antibodies (AHA), which may act as surrogate Fc domains and restore effector function. Because Fab-based therapeutics are often designed specifically to eliminate effector function, such restored effector function poses potential safety risks. See paragraph [0005] of the published application. The present application demonstrates that these risks are mitigated through a specific structural modification-termination of the IgG1 Fab at residue D221. As shown in FIG. 1B and described in paragraphs [0013] and [0140] of the present application, terminating the IgG1 Fab at D221, reduces AHA binding to near-background levels. See paragraphs [0013] and [0140] of the published application. Further, FIG. 1C and paragraph [0139] show that reduced AHA binding is consistently observed across multiple Fab constructs with different antigen binding domains, confirming that the effect is driven by the termination at D221 rather than antigen binding.
Additional support is provided in paragraph [0153] of the instant application, which discloses that removal of the unstructured upper hinge region by truncation at D221 minimizes the risk of generating neoepitopes susceptible to exopeptidase activity and subsequent AHA recognition. This structural modification thus preserves a natural antibody sequence while significantly improving safety by reducing unintended immune interactions. See paragraphs [0237] and [0363] of the published application. Accordingly, the claims are directed to a construct consisting of a structurally defined antibody fragment with demonstrated functional advantages arising from that structure and not to the antigen binding domain.
Based on the foregoing disclosures, one skilled in the art would understand that the Applicant was indeed in possession of the claimed subject matter and would recognize that the specification sets forth "an adequate description that 'in a definite way identifies the claimed invention' in sufficient detail that a person of ordinary skill would understand that the inventor had made the invention at the time of filing." Allergan, Inc. v. Sandoz Inc., 796 F.3d 1293, 1308 (Fed. Cir. 2015) (citing Ariad, 598 F.3d at 1352). Accordingly, Applicant submits that the written description requirement is satisfied.
In response to the argument that claim 1 of the present application is directed to a construct consisting of an isolated IgG1 Fab antibody fragment defined by specific structural features, e.g., terminates with residue D221 according to EU numbering, the claim encompasses any and all possible mammalian IgG1 Fab antibody. The specification discloses just human IgG1 Fab that terminates at residue D221, see para. [0013], [0017], [0034], [0124]. Further, a Fab fragment comprising a light chain fragment comprising a VL domain and a constant domain of a light chain (CL), and a VH domain and a first constant domain (CH1) of a heavy chain. The specification discloses:
The recombinant expression of Fab molecules in E. coli and mammalian cells allows to readily produce molecules with defined C-terminal ends without the need of proteolytic cleavage. To ensure integrity of the C-terminus, correct mass of the purified Fab was confirmed by intact mass-spectrometry. The Fab molecules were coated on microtiter plates, and after incubation with pooled human donor serum, binding of pre-existing AHA was quantified by anti-Fc detection. In agreement with the previous study (20), T.sub.223 at the C-terminus (having the sequence DKT, also referred to herein as “CDKT” (SEQ ID NO: 17)) showed the highest reactivity of all upper hinge variants towards pre-existing AHA (FIG. 1B). Significant difference to the previous studies is observed with T.sub.225 at the C-terminus (having the sequence DKTHT (SEQ ID NO: 21), also referred to herein as “CDKTHT” (SEQ ID NO: 14)). This variant did not bind AHA as peptide (20); however, substantial AHA reactivity was observed when tested as Fab. With D.sub.221 at the C-terminus (having the sequence D, also referred to herein as “CD”), binding of AHA was reduced almost to background. Thus, terminating the Fab at D.sub.221 provides a solution to minimize recognition by pre-existing AHA while maintaining a natural antibody sequence.
However, the specification does not describe the structure, e.g., amino acid sequences of all possible VL domain and VH domain encompassed by the claimed IgG1 Fab antibody fragment that terminates with residue D221, numbering according to EU.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
In this case, the disclosure of just human IgG1 Fab that terminating at residue D221 to minimize recognition of pre-existing human antibodies to the Fab of human IgG1 is not a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
Regarding pharmaceutical formulation (claim 22), the specification does not describe the structure, e.g., amino acid sequence of heavy and light chain variable domains of all possible IgG1 Fab that terminates at residue D221 and correlated with binding to which target antigen, in turn, effective for treating which disease. A pharmaceutical formulation in the absence of in vivo working example is unpredictable.
Regarding antibody-drug conjugate (claim 29), there are no objective evidences of any antibody-drug conjugate comprising the claimed construct consisting of any IgG1 Fab antibody that terminates with residue D211 according to EU numbering conjugated to any and all cytotoxic agent.
The state of the prior art is such that the location or site of conjugation on the drug and the antibody or Fab fragment affect conjugate stability, and pharmacokinetics of antibody drug conjugates.
For example, Strop et al (of record, Chemistry and Biology 20: 161-167, 2013; PTO 892) teach drug position can have a significant effect on linker stability and antibody pharmacokinetics. The site of conjugation on the drug and antibody can influence ADC properties differently in mice and rats, highlighting potential pitfalls of examining efficacy in mouse xenograft models and toxicity in rats or nonhuman primates, see abstract, p 166, p. 168 right col, in particular.
Nejadmoghaddam (of record, Avicenna Journal of Medical Biotechnology 2(1): 3-23, 2019; PTO 892) discusses major obstacles of antibody-drug conjugates include off-target toxicity, tumor marker selection, antibody specificity, adequately affinity and receptor-mediated internalization are major aspects of choice, cytotoxic payload (e.g., up to 7 drugs per antibody), cytotoxic payload linkage strategy, aqueous solubility, non-immunogenic and stability in storage and bloodstream, see entire document, abstract, p. 15, in particular.
There are no in vivo working examples. It is unpredictable which undisclosed IgG1 Fab antibody fragment that terminates with residue D221 is effective as a pharmaceutical composition for treating which disease. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus of IgG1 Fab antibody fragment that terminates with residue D221 according to EU numbering or antibody-drug conjugate thereof or pharmaceutical formulation thereof as broadly claimed.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) (Claims directed to PTFE dental floss with a friction-enhancing coating were not supported by a disclosure of a microcrystalline wax coating where there was no evidence in the disclosure or anywhere else in the record showing applicant conveyed that any other coating was suitable for a PTFE dental floss.) On the other hand, there may be situations where one species adequately supports a genus. See, e.g., Rasmussen, 650 F.2d at 1214, 211 USPQ at 326-27 (disclosure of a single method of adheringly applying one layer to another was sufficient to support a generic claim to "adheringly applying" because one skilled in the art reading the specification would understand that it is unimportant how the layers are adhered, so long as they are adhered); In re Herschler, 591 F.2d 693, 697, 200 USPQ 711, 714 (CCPA 1979) (disclosure of corticosteroid in DMSO sufficient to support claims drawn to a method of using a mixture of a "physiologically active steroid" and DMSO because "use of known chemical compounds in a manner auxiliary to the invention must have a corresponding written description only so specific as to lead one having ordinary skill in the art to that class of compounds. Occasionally, a functional recitation of those known compounds in the specification may be sufficient as that description."); In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 285 (CCPA 1973) (the phrase "air or other gas which is inert to the liquid" was sufficient to support a claim to "inert fluid media" because the description of the properties and functions of the air or other gas segmentizing medium would suggest to a person skilled in the art that appellant’s invention includes the use of "inert fluid" broadly.).
A “patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”), see MPEP 2163.IIAii
Finally, ppossession may not be shown by merely described how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895.
For these reasons, the rejection is maintained.
Claims 1, 6, 20, 22, 25-26 and 29 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 (1) a construct consisting of an isolated human IgG1 Fab antibody fragment from abciximab that binds to platelet surface receptor GPIIb/IIIa wherein the Fab antibody fragment terminates with residue D211 according to EU numbering, wherein the IgG1 Fab antibody fragment has reduced or no reactivity towards pre-existing human anti-hinge antibodies, (2) Said construct, wherein the IgG1 Fab antibody fragment comprises a heavy chain constant region that consists of the amino acid sequence set forth in SEQ ID NO: 6, (3) a pharmaceutical composition comprising said construct and a pharmaceutically acceptable carrier, does not reasonably provide enablement for any construct as set forth in claims 1, 6, 20, 22, 25-56 and 29. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re wands, 858 F.2d 731, 737.8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 1 encompass any construct consisting of any isolated IgG1 Fab antibody fragment that terminates with residue D221, according to EU numbering, wherein the IgG1 Fab antibody fragment has reduced or no reactivity towards pre-existing anti-hinge antibodies.
Claim 6 encompasses the construct of claim 1, wherein the IgG1 Fab antibody fragment terminates with amino acids CD.
Claim 20 encompasses the construct of claim 1, wherein the IgG1 Fab antibody fragment comprises a heavy chain constant region that consists of the amino acid sequence set forth in SEQ ID NO: 6 and any conservative modifications thereof.
Claim 22 encompasses a pharmaceutical formulation comprising the construct of claim 1 and a pharmaceutically acceptable carrier.
Claim 25 encompasses a pharmaceutical formulation comprising the construct of claim 6 and a pharmaceutically acceptable carrier.
Claim 26 encompasses a pharmaceutical formulation comprising the construct of claim 20 and a pharmaceutically acceptable carrier.
Claim 29 encompasses any antibody-drug conjugate comprising any construct consisting of any isolated IgG1 Fab antibody fragment that terminates with residue D221 according to EU numbering conjugated to any cytotoxic agent.
The specification discloses therapeutic Fab molecule directed against platelet surface receptor GPIIb/IIIa (abciximab, REOPRO®) is commercially produced by proteolytic cleavage with papain (5), which is the original method of Fab production (6). With the advances in molecular cloning, recombinant expression of antibody fragments has become an attractive route to generate Fab molecules as exemplified by the second approved Fab therapeutic, anti-VEGF (ranibizumab, Lucentis®) (7) and the recently approved Fab against dabigatran (idarucizumab, Praxbind®), see para. [0004]. The C-terminus of an antibody fragment disclosed herein, e.g., a Fab fragment, terminates at amino acid residue D.sub.221 (according to EU numbering), see para. [0065]. One therapeutic Fab molecule directed against platelet surface receptor GPIIb/IIIa (abciximab, REOPRO®) is commercially produced by proteolytic cleavage, see para. [0081].
However, the specification does not teach i. Complete structure, e.g., amino acid sequences of heavy and light chains variable domains, or ii. Partial structure, e.g., six CDRs of IgG1 Fab that terminates at residue D221 that correlated with binding share by members of the genus as a pharmaceutical composition (claims 22, 25 and 26). Notably, the specification, does not teach the structure, e.g., amino acid sequence of the heavy and light chain variable domains that correlated with binding to all antigens.
It is known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 334(1): 103-118, 2003; PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla et al (of record, Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Given that hundreds of unique antibody Fab structures may bind a single antigen, the structure of an antibody Fab cannot be predicted from the structure of the antigen, and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen.
Regarding antibody-drug conjugate (claim 29), there are no objective evidences of any antibody-drug conjugate comprising the claimed construct consisting of any IgG1 Fab antibody that terminates with residue D211 according to EU numbering conjugated to any and all cytotoxic agent.
The state of the prior art is such that the location or site of conjugation on the drug and the antibody or Fab fragment affect conjugate stability, and pharmacokinetics of antibody drug conjugates.
For example, Strop et al (of record, Chemistry and Biology 20: 161-167, 2013; PTO 892) teach drug position can have a significant effect on linker stability and antibody pharmacokinetics. The site of conjugation on the drug and antibody can influence ADC properties differently in mice and rats, highlighting potential pitfalls of examining efficacy in mouse xenograft models and toxicity in rats or nonhuman primates, see abstract, p 166, p. 168 right col, in particular.
Nejadmoghaddam (of record, Avicenna Journal of Medical Biotechnology 2(1): 3-23, 2019; PTO 892) discusses major obstacles of antibody-drug conjugates include off-target toxicity, tumor marker selection, antibody specificity, adequately affinity and receptor-mediated internalization are major aspects of choice, cytotoxic payload (e.g., up to 7 drugs per antibody), cytotoxic payload linkage strategy, aqueous solubility, non-immunogenic and stability in storage and bloodstream, see entire document, abstract, p. 15, in particular.
There are no working examples. It is unpredictable which undisclosed IgG1 Fab antibody fragment that terminates with residue D221 is effective as a pharmaceutical composition for treating any and all diseases. As such, it would require undue experimentation of one skilled in the art to practice the claimed invention.
Applicant's arguments filed March 27, 2026 have been carefully considered but are not found persuasive.
Applicant’s position is that claim 1 is directed to a construct consisting of an isolated IgG1 Fab antibody fragment having particular structural features and associated benefits, irrespective of the antigen to which it can bind. The claims are therefore directed to a structurally defined IgG1 Fab construct, not a functionally defined genus of antibodies that bind to an antigen.
The present application identifies and describes the common structural feature that delineates the claimed subject matter, i.e., the truncation at D221. It is this common structural feature, not the antigen-binding domain, that results in the disclosed advantages. As shown in FIG. lA and described in paragraphs [0013] and [0140], termination at D221 reduces AHA binding to near-background levels. Further, FIG. 1C and paragraph [0139] demonstrate that this effect is consistent across multiple Fab constructs having different antigen-binding domains. Therefore, the present application enables the full scope of the claimed subject matter without undue experimentation because it provides clear and reproducible structural guidance-namely, truncation at D221.
Based on the foregoing disclosures, Applicant respectfully submits that claim 1, and claims dependent therefrom, are enabled at least because, in view of the application as a whole, a person of ordinary skill would be fully enabled to practice the claims without undue experimentation. Accordingly, Applicant submits that the enablement requirement is satisfied.
In response, the enablement requirement refers to the requirement of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph that the specification describe how to make and how to use the invention, not just how to make the invention, see MPEP 2164.
In response to the argument that claim 1 of the present application is directed to a construct consisting of an isolated IgG1 Fab antibody fragment defined by specific structural features, e.g., terminates with residue D221 according to EU numbering, the claim encompasses any and all possible mammalian IgG1 Fab antibody. The specification discloses just human IgG1 Fab that terminates at residue D221, see para. [0013], [0017], [0034], [0124]. Further, a Fab fragment comprising a light chain fragment comprising a VL domain and a constant domain of a light chain (CL), and a VH domain and a first constant domain (CH1) of a heavy chain.
However, the specification does not teach the structure, e.g., amino acid sequences of all possible VL domain and VH domain encompassed by the claimed IgG1 Fab antibody fragment that terminates with residue D221, numbering according to EU as a pharmaceutical formulation for treating any and all disease.
It is known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (of record, Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; see, e.g., Discussion).
Similarly, Edwards et al., (of record, J Mol Biol. 334(1): 103-118, 2003; PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla et al (of record, Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Given that hundreds of unique antibody Fab structures may bind a single antigen, the structure of an antibody Fab cannot be predicted from the structure of the antigen, and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen.
Regarding antibody-drug conjugate (claim 29), there are no objective evidences of any antibody-drug conjugate comprising the claimed construct consisting of any IgG1 Fab antibody that terminates with residue D211 according to EU numbering conjugated to any and all cytotoxic agent is effective for treating all possible disease.
The state of the prior art is such that the location or site of conjugation on the drug and the antibody or Fab fragment affect conjugate stability, and pharmacokinetics of antibody drug conjugates.
For example, Strop et al (of record, Chemistry and Biology 20: 161-167, 2013; PTO 892) teach drug position can have a significant effect on linker stability and antibody pharmacokinetics. The site of conjugation on the drug and antibody can influence ADC properties differently in mice and rats, highlighting potential pitfalls of examining efficacy in mouse xenograft models and toxicity in rats or nonhuman primates, see abstract, p 166, p. 168 right col, in particular.
Nejadmoghaddam (of record, Avicenna Journal of Medical Biotechnology 2(1): 3-23, 2019; PTO 892) discusses major obstacles of antibody-drug conjugates include off-target toxicity, tumor marker selection, antibody specificity, adequately affinity and receptor-mediated internalization are major aspects of choice, cytotoxic payload (e.g., up to 7 drugs per antibody), cytotoxic payload linkage strategy, aqueous solubility, non-immunogenic and stability in storage and bloodstream, see entire document, abstract, p. 15, in particular.
There are no in vivo working examples. It is unpredictable which undisclosed IgG1 Fab antibody fragment that terminates with residue D221 is effective as a pharmaceutical composition for treating any and all diseases.
As such, undue experimentation is required to practice the claimed invention commensurate in scope with the claims.
For these reasons, the 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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
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 571-272-0839.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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