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 .
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 9/23/2022, 9/27/2022, 2/17/2023, 11/11/2024, and 5/21/2025 are acknowledged and the references cited therein have been considered.
Priority
The present application is a 371 National Stage Application of PCT International Application No. PCT/EP2021/057946, filed 3/26/2021, which claims the benefit of Great Britain Patent Application No. GB2008095.8, filed 5/29,2020, and Great Britain Patent Application No. GB2004462.4, filed 3/27/2020. Applicant' s claim for the benefit of prior-filed application is acknowledged.
Status of Claims
Applicant’s Response to Election/Restriction received 10/06/2025 is acknowledged.
Claims 1, 2, 4, 6, 8, 11, 14, 15, 16, 17, 18, 23, 28, 29, 30, 32, 33, 34, 35, 44, 50, 52, 56, 57, and 58 are pending in the instant application.
Claims 3, 5, 7, 9, 10, 12, 13, 19-22, 24-27, 31, 36-43, 45-49, 51, and 53-55 have been canceled.
Claims 1, 2, 4, 6, 8, 11, 14, 16, 18, 23, and 30 have been amended.
Claims 57 and 58 are new.
Applicant’s election of Group 1, claims 1-2, 4, 6,8 11, 14-17, 28 (now 1-2, 4, 6,8 11, 14-17, 28-30, 57 and 58) directed to an isolated antibody fragments polypeptides, comprising them and compositions comprising them and the species of SEQ ID NO: 322 and (AB)N motif in the reply filed on 10/06/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 17, 29, 32-35, 44, 50, 52, and 56 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species (17, 29) or nonelected group (32-35, 44, 50, 52, 56), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/06/2025.
Claims 1, 2, 4, 6, 8, 11, 14, 15, 16, 18, 23, 28, 30, 57, and 58 are under consideration as they read on SEQ ID NO: 322 and (AB)N motif.
Claims 1, 6, 8, 11, 14, 15, 16, 18, 23, 28 are objected to under 37 CFR 1.75(c) because it is improper dependent claim since it fails to refer back to an earlier claim. Rather claim 1, 6, 8, 11, 14, 15, 16, 18, 23, 28 refer back to a proceeding claim 57. 37 CFR 1.75(c) states: (c) One or more claims may be presented in dependent form, referring back to and further limiting another claim or claims in the same application.
Claim Rejections - 35 USC § 112
Enablement
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.
Claims 1, 2, 4, 6, 8, 11, 14, 15, 16, 18, 23, 28, 30, 57, and 58 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 SEQ ID NO: 322, 334, 336, 317, 339, and 313, does not reasonably provide enablement for an isolated antibody fragment which binds to an antigen of interest and which comprises a sequence of the knob domain of a bovine ultralong CDR-H3 or a portion or a variant thereof and which does not comprise the stalk domain of the bovine ultralong CDR-H3 of claim 57; wherein the fragment is the knob domain of a bovine ultralong CDR-H3 or a portion thereof of claim 1; which comprises at least two, or at least four, or at least six, or at least eight, or at least ten cysteine residues and/or comprises at least one, or at least two, or at least three, or at least four, or at least five disulphide bonds of claim 2; an isolated antibody fragment according to claim 1 which comprises a (Z1) X₁ C X₂ motif at its N-terminal extremity, wherein: a. Z₁ is present or absent, and when Z₁ is present, Z₁ represents 1 amino acid or 2, 3, 4, or 5 independently selected amino acids; and, b. X₁ is any amino acid residue, preferably selected from the list consisting of Serine, Threonine, Asparagine, Alanine, Glycine, Proline, Histidine, Lysine, Valine, Arginine, Isoleucine, Leucine, Phenylalanine and Aspartic acid; and, c. C is cysteine; and, d. X₂ is an amino acid selected from the list consisting of Proline, Arginine, Histidine, Lysine, Glycine and Serine; and/or wherein said isolated antibody fragment comprises a (AB)n and/or (BA)n motif, wherein A is any amino acid residue, B is an aromatic amino acid selected from the group consisting of: tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), and wherein n is 1, 2, 3 or 4 of claim 4; which is 5 amino acids in length or more, 10 amino acids in length or more, 15 amino acids in length or more, 20 amino acids in length or more, 25 amino acids in length or more, 30 amino acids in length or more, 35 amino acids in length or more, 40 amino acids in length or more, 45 amino acids in length or more, and which is up to 55 amino acids in length of claim 6; which further comprises a bridging moiety between two amino acids of claim 8; is fully bovine, chimeric, or synthetic of claim 11; wherein the antigen of interest is the component C5 of the Complement of claim 14; which has a sequence selected from the list consisting of SEQ ID NO: 157 to SEQ ID NO: 310, SEQ ID NO:313, SEQ ID NO: 315, SEQ ID NO: 317, SEQ ID NO: 318, SEQ ID NO: 320, SEQ ID NO: 322, SEQ ID NO: 324, SEQ ID NO: 326 to SEQ ID NO: 331, SEQ ID NO: 334, SEQ ID NO: 336, SEQ ID NO: 339, SEQ ID NO: 341 to SEQ ID NO: 350, SEQ ID NO: 352, and SEQ ID NO: 572 to SEQ ID NO: 609 or any one of the same with at least 95%, 96%, 97%, 98% or 99% similarity or identity of claim 15; wherein the antigen of interest is human serum albumin of claim 16; a polypeptide comprising at least one isolated antibody fragment as defined in claim 57 of claim 18; wherein said fragment or polypeptide is fused to one or more effector molecules, optionally via a linker of claim 23; wherein the effector molecule is albumin or a protein comprising an albumin binding domain of claim 28; a pharmaceutical composition comprising an isolated antibody fragment as defined in claim 1 or a polypeptide comprising the isolated antibody fragment in combination with one or more of a pharmaceutically acceptable excipient, diluent or carrier of claim 30; a polypeptide comprising at least two isolated antibody fragments as defined in claim 57, wherein the antibody fragments are optionally linked together by a linker. 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.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
Though the term ‘isolated antibody fragment’ of claim 57 is defined in the instant specification, it is overly broad and therefore not enabled to be made or used. For example, the specification does not specify a means of production for the isolated antibody fragment (simply states “may be produced recombinantly or synthetically”), which would entail undue experimentation.
The claims are directed to a broad class of antibodies and that class was defined by its function—the ability to bind to antigens of interest/C5/HSA. However, the specification did not give the skilled in the art enough information to choose candidate bovine ultralong HCDR3 knob domain antibody fragments from the millions of options and therefore required scientists to engage in a great deal of experimentation and failure. “That is not enablement”—it is a “hunting license.”
In Sanofi-Aventisub, the Federal Circuit relied on its prior precedential opinions when determining whether the full scope of a genus was enabled. These decisions included McRO, Inc. v. Bandai Namco Games Am. Inc., 959 F.3d 1091 (Fed. Cir. 2020) (hereafter McRO); Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380 (Fed. Cir. 2013) (hereafter Wyeth); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340 (Fed. Cir. 2019) (hereafter Enzo); and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149 (Fed. Cir. 2019) (hereafter Idenix).
The Federal Circuit, citing McRO, provided guidance on the application of enablement to genus claims, holding that “[a]lthough a specification does not need to describe how to make and use every possible variant of the claimed invention, when a range is claimed, there must be reasonable enablement of the scope of the range.” Sanofi-Aventisub, 987 F.3d at 1085 (internal quotations omitted). Additionally, the Federal Circuit characterized Wyeth as holding “that due to the large number of possible candidates within the scope of the claims and the specification's corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the claimed functionality.” Id. at 1086. Similarly, the Federal Circuit characterized Enzo as holding “that the specification failed to teach one of skill in the art whether the many embodiments of the broad claims would exhibit that required functionality.” Id. Finally, the Federal Circuit characterized Idenix as affirming “the district court's determination that the claims had both structural and functional limitations, and that undue experimentation would have been required to synthesize and screen the billions of possible compounds because, given a lack of guidance across that full scope, finding functional compounds would be akin to finding a `needle in a haystack.' ” Id.
This case is akin to the issue in Sanofi-Aventisub, the court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. While the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class that included “a `vast' number of additional antibodies” that Amgen had not described by their amino acid sequences. Id. at 1256. The Supreme Court found that Amgen sought to monopolize an entire class of antibodies by their function, which was much broader than the 26 exemplary antibodies disclosed by their amino acid structure. In the instant case, the specification discloses K8, K57, K60, K92, K136, and K149 that binds human/mouse/rabbit C5 species that performed the claimed function by their amino acid sequences, with the claimed genus of millions of different bovine ultralong HCDR3 anti-antigen/C5/HSA antibody fragments knob domain. The instant claims are directed to a class of bovine ultralong HCDR3 anti-antigen/C5/HSA antibody fragments knob domain that included “a `vast' number of additional antibodies” that the instant specification fails to describe their amino acid sequences.
The scope of the instant claims encompassed millions of bovine ultralong HCDR3 anti-antigen/C5/HSA antibody fragments knob domain and that it was necessary to first generate and then screen each candidate to determine whether it met the functional limitations. The Federal Circuit concluded that there was a lack of enablement, which was affirmed by the Supreme Court in Amgen.
The claims simply direct skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the six antibodies they elected to disclose and that “[u]nder Amgen, such random trial-and-error discovery, without more, constitutes unreasonable experimentation that falls outside the bounds required by § 112(a).” Id. at *8, *10.
Amgen attempted to claim an entire class of compounds by their function, namely antibodies that bind to the “sweet spot” of PCSK9 thereby inhibiting it from binding to LDL, while only describing 26 amino acid sequences in its specification. The two processes, the “roadmap” and “conservative substitution” did not save Amgen. According to the Court, these amounted to “little more than two research assignments” which forced scientists to conduct “painstaking experimentation” to see what worked. (citing Incandescent Lamp). The Court therefore held that Amgen’s specification did not enable the claims.
In terms of binding an ‘antigen of interest’ – at its broadest, this language would be taken to mean any antigen of interest. This is not enabled in the instant specification, as the instant specification is only enabled for two specific antigens of interest (C5 of the Complement, and human serum albumin).
The isolated antibody fragment is stated to comprise ‘a sequence of the knob domain of a bovine ultralong CDR-H3 or a portion or a variant thereof and which does not comprise the stalk domain of the bovine ultralong CDR-H3’, however there is excessive experimentation necessary to make and use the invention. This is due to the diversity of CDR-H3 length and structure, as evidenced by Wang et al (IDS NPL #7, Submitted 9/23/2022). This diverse structure is specifically seen in the cysteine content and disulphide bond arrangement of the knob domain, as well.
In the context of the instant specification, another motif which is not enabled in the isolated antibody fragment is the ‘(Z1) X₁ C X₂ motif at its N-terminal extremity, wherein: a. Z₁ is present or absent, and when Z₁ is present, Z₁ represents 1 amino acid or 2, 3, 4, or 5 independently selected amino acids; and, b. X₁ is any amino acid residue, preferably selected from the list consisting of Serine, Threonine, Asparagine, Alanine, Glycine, Proline, Histidine, Lysine, Valine, Arginine, Isoleucine, Leucine, Phenylalanine and Aspartic acid; and, c. C is cysteine; and, d. X₂ is an amino acid selected from the list consisting of Proline, Arginine, Histidine, Lysine, Glycine and Serine; and/or wherein said isolated antibody fragment comprises a (AB)n and/or (BA)n motif, wherein A is any amino acid residue, B is an aromatic amino acid selected from the group consisting of: tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), and wherein n is 1, 2, 3 or 4’, as stated in claim 4. This is not enabled due to overly broad claim, and the structure would not correlate to any function. Given the diversity of structure and length of bovine CDR-H3s, instant claim 6 is also not enabled due to breadth of claim.
In the context of comprising a bridging moiety between two amino acids, instant claim 8 is not enabled due to breadth of claim.
For instant claim 11, there is an absence of working examples, as the only examples in the instant specification are fully bovine or synthetic. The instant claim, however, reads on fully bovine, chimeric, or synthetic isolated antibody fragments.
The instant claim 15 recites the limitation “or any one of the same with at least 95%, 96%, 97%, 98% or 99% similarity or identity”. A change of 1% to 5% in the amino acid sequence of a polypeptide could render it inactive or completely change its activity profile. Thus, the instant application is not enabled for the range of 95%-99% similarity or identity.
Instant claim 18 recites “a polypeptide comprising at least one isolated antibody fragment as defined in claim 57”. Since it uses language including “comprising”, this claim is too broad in scope, and thus not enabled.
In the instant claim 23, it is recited that “said fragment or polypeptide is fused to one or more effector molecules, optionally via a linker”. In Example 7.1 of the instant specification, human and rat albumin knob domain fusion proteins are disclosed. These fusion proteins incorporated knob domain peptides, flanked by a linker sequence. There was, however, very little direction or guidance presented for one of skill in the art.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
Written Description
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.
Claims 1, 2, 4, 6, 8, 11, 14, 15, 16, 18, 23, 28, 30, 57, and 58 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. (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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1, 57 encompasses a broad genus of antibody fragments that binds to any antigen of interest and comprises the knob domain of a bovine ultralong CDR-H3 sequence, a genus of portions and a genus of variants of the bovine ultralong CDR-H3.
Claim 2 encompasses a genus of antibody fragments comprising up to 10 cysteine residues or up to 5 disulphide bonds out of 45 amino acid presents in the knob domain of the bovine ultralong CDR-H3 (e.g., SEQ ID NO: 45).
Claim 4 encompasses antibody fragments that comprising a genus of motif that comprises up to 5 unknown independent amino acids (Z1), one unknown amino acid (X1) , Cysteine (C) and either P, R, H, K, G or S (X2) and/or comprising a genus of (AB)n and/or (BA)n motif, wherein A is any amino acid residue, B is selected from Y, F, W or H, and wherein n is up to 4.
Claim 6 encompasses a genus of antibody fragments that comprises from 5 up to 55 amino acids length
Claim 15 encompasses antibody fragments comprising up to 5% modification in SEQ ID NO: 322.
However, there does not appear to be an adequate written description in the specification as-filed of the essential structural feature that provides the recited function of antibody fragments binding any antigen/C5/HSA. The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement make clear 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, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus.
The claims encompass a broad genus of antibody fragments that binds to a broad genus of antigen.
The USPTO has released a Memo on the Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018.
See https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf.
The Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies, including the following.
“In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional”.
In contrast to applicant’s reliance of describe the epitope of an antigen of interest in providing a fully characterized antigen / specific epitope as well as claiming structural elements of the antigen, complement C5 and human serum albumin,
there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed bovine ultralong HCDR3 antibody fragments that bind antigen to demonstrate possession. Also, see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017).
There is no evidence that knowledge of the chemical structure of an antigen gives the required kind of structure identifying information about the corresponding bovine ultralong HCDR3 antibody fragments knob domain Applicants attempt to describe the invention by describing something that is not the invention: viz., the antigens to which the antibodies may bind. There nothing in the disclosure that describes the antibodies as required by the test set forth in Ariad.
However, the anti-antigen/C5/HSA antibody fragments are required to practice the invention. The specification fails to provide any specific structural or physical information so as to define a genus of antibodies having the desired therapeutic properties. Applicant is merely relying on the identification of antigen/C5/HSA as the antigen and the well-known structure of bovine ultralong HCDR3 antibody fragments in general. However, the claims do not recite a general antibody, but an antibody having a specific desired activity. However, Federal Circuit clarification of the law of written description as it applies to antibodies. Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017).
The claims are directed to a genus of bovine ultralong HCDR3 antibody fragments that bind to any antigen/C5/HSA. However, Federal Circuit clarification of the law of written description as it applies to antibodies. The U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) 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 Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed bovine ultralong HCDR3 antibody fragments knob domain that bind to any antigen/C5/HSA to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). The Court reiterated that adequate written description must “contain enough information about the actual makeup of the claimed products . . . .” The Court simultaneously suggested that the “newly characterized antigen” test “flouts” section 112 because it “allows patentees to claim antibodies by describing something that is not the invention, i.e. the antigen.” The Court concluded that for written description of an antibody to be adequate when presented with “functional” terminology, there must be an established correlation in the art between structure and function.
For instance, citing to Centocor, the Court analogized an antigen and antibody to a lock and a key. For an antigen where there is only a finite number of binding antibodies, discovering those antibodies may be routine and conventional, and description of the antigen alone may be sufficient. By contrast, for antigens with millions of keys, or millions of potentially binding antibodies, description of the antigen and even a couple of examples may be far from sufficient.
"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)) (emphasis added).
"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" (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
Possession is not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Sufficient description to show possession of such a genus may be achieved by means of a recitation of a representative number of bovine ultralong CDR-H3 antibody fragments, portions or antibody variants falling within the scope of the genus or of a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. See Eli Lilly, 119F.3d at 1568, 43 USPQ2d at 1406.
With respect to representative number of species of the claimed genus bovine ultralong HCDR3 antibody fragments that bind a genus of antigens. With respect to representative number of species,
see AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014)
Also, see MPEP 2163 II(A)(3)(a))(ii):
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. 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 instant specification discloses six primary examples: K8, K57, K60, K92, K136, and K149 (see pages 114-118 of the instant specification). The Applicant discloses the amino acid sequences of K8 (SEQ ID NO: 322), K57 (SEQ ID NO: 334), K60 (SEQ ID NO: 336), K92 (SEQ ID NO: 317), K136 (SEQ ID NO: 339), and K149 (SEQ ID NO: 313). Each of the knob domain peptides bound human C5 with high affinity, except K60 (see Table 11, page 118). Both K8 and K92 were cross reactive to mouse and rabbit C5 as well (see Table 12, page 119).
It is noted that the broadest claim (claim 57) does not indicate any specific structure for the genus of isolated antibody fragments claimed. The term “any portion or a variant thereof” or “antibody fragment” reads on any 2 or more amino acid sequence, and any “comprising” language opens the claims to include any number of additional amino acids, all giving unpredictable function such that there is no structure/function correlation.
Indeed, claim 15 does recite specific sequence of isolated antibody fragment, however it also recites the limitation “or any one of the same with at least 95%, 96%, 97%, 98%, or 99% similarity or identity.” Claim 15 does not satisfy written description also, because the claim language uses the word similarity, which allows for too much variability in the amino acid structure (i.e., sequence similarity is a less stringent bar of measurement than sequence identity).
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112 § 1 “Written Description” Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus (Federal Register, Vol 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3).
Regarding the state of the art, it has been well established that there is extensive diversity in the cow ultralong CDRH3 antibody knob domain repertoire, especially in terms of structure (see Haakenson et al., Front. Immunol. 9:1262;1-10 (2018), IDS NPL Reference #2, Submitted 9/23/2022, and Wang et al., Cell June 6; 153(6): 1379-1393 (2013), IDS NPL Reference #7, Submitted 9/23/2022). As such, it does not seem possible to predict the sequence/structure of an isolated antibody fragment that binds a given antigen, as there does not appear to be common or core structure present within all fragments that gives rise to the function of antigen binding. Taken together, the art suggests that identifying isolated antibody fragments of bovine ultralong CDRH3 origin which bind a specific antigen is highly unpredictable. Further, given such data as that of Haakenson et al. and Wang et al., no number of representative species appears to be reasonably representative of the breadth of the genus of isolated antibody fragments that bind the given antigen (C5 of the Complement and human serum albumin, in the instant case).
From Haakenson et al.: “Although these ultralong CDR H3 antibodies share the general “stalk & knob” scaffold, each antibody also possesses distinct structural variations in the CDR H3 (Figure 1C). These structural variations are reflected in differences in the length of the stalk and the orientation of the knob relative to the rest of the antibody structure (25). For example, the stalk length of BLV1H12 is the longest among these five antibodies, while the stalk length of A1 is the shortest (25). When the five Fab structures are superimposed by the shared type I β-turn and the three antiparallel β strands in the knob region, obvious differences in stalk positions are observed, reflecting different knob orientations that are supported by the stalks (25). Furthermore, as the number and positions of cysteine residues in the knob region differ significantly among these cow ultralong antibodies, each of them possesses a knob region with unique disulfide bond patterns (25). Therefore, different stalk lengths, knob orientations, and disulfide bond patterns, in addition to diverse amino acid content within the knob regions of these antibodies provide remarkable structural diversity generated in the bovine ultralong CDR H3 antibody repertoire.” Taken together, any of the listed changes make antigen binding unpredictable.
From Macpherson et al. (PLOS Biology 18(9):1-14 (2020), IDS NPL #3, Submitted 9/23/2022): “From our initial screening with CDRH3-ScFc constructs, we observed a 27% hit rate for C5 binding. While entirely practicable for knob domain discovery, the attrition at this stage may indicate that not all ultralong CDRH3 can function entirely independently of their parent antibody. Previous studies have suggested that the β-ribbon stalk of an ultralong CDRH3 is obligate to orientate the knob domain peptide [6–8, 38]. Inspection of bovine Fab structures in the Protein Data Bank (PDB) frequently reveals stabilising interactions between the knob domain peptide and the β-ribbon stalk, and numerous interactions between the β-ribbon stalk and neighbouring CDRs and VH framework residues [6–8]. In one recent structure (BOV-7, PDB accession code: 6E9U [7]), a disulphide bond was observed between cysteine residues of the stalk and knob domain [7]. Therefore, for certain ultralong CDRH3, removal of the stalk may in turn remove critical interactions required to stabilise the knob domain.” This indicates there is a need to screen for CDRH3s which can independently bind antigen. There is no structure/function correlation.
Thus, one of ordinary skill in the art cannot envision from the disclosed species provided, the breadth of isolated antibody fragment of the instant invention comprising: any isolated antibody fragment which binds to any antigen of interest and which comprises any sequence of the knob domain of a bovine ultralong CDR-H3 or any portion or a variant thereof and which does not comprise the stalk domain of the bovine ultralong CDR-H3.
Therefore, in view of the breadth of the claims and the limitations of the instant specification, artisans would reasonably conclude that Applicant was not in possession of the full breadth of isolated antibody fragments encompassed by the claims at the time the instant application was filed.
Claim Rejections - 35 USC § 102
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 following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 4, 8, 11, 18, 30, 57 and 58 are rejected under 35 U.S.C. 102a(1) as being anticipated by Sok et al (Nature 548, 108–111 (2017), IDS NPL #1, Submitted 11/11/2024).
Sok et al investigated whether the cow1 (i.e., bovine) HCDR3 knob (i.e., antibody fragment) is functional on its own (i.e., lacks stalk domain) and whether the antibody retains its function when reverted to its inferred germline. Sok et al evaluated NC-Cow1 for neutralization on the 12-virus (antigen) indicator panel, which demonstrated 100% breadth at a potent median IC50 of 0.007 μ g ml−1 (Fig. 3d). Compared to this affinity- matured antibody, partial or fully reverted antibody variants showed no or little decrease in neutralization breadth and potency (Fig. 3d). Sok et al next transplanted the 60-amino-acid HCDR3 of NC-Cow1 to a germline-reverted variant of HIV bnAb PG9 and tested for neutralization on the 12-virus indicator panel. They observed a moderate drop to 88% neutralization breadth with a reduction in potency to a median IC50 of 0.054 μ g ml−1. Although less active than the original antibody, the neutralization breadth and potency of a 60-amino acid HCDR3 knob transplanted onto a germline antibody is remarkable, and may have implications for therapeutic designs (see pages 109-110, bridging ¶).
Claim 2 is included because Fig. 3A shows that the HCDR3 know has 6 cysteine residues.
Claim 4 is included because Fig. 3A shows the motif KTNKKECP, wherein Z1 is KTNKK, X1 is E, and X2 is P and/or the motifs DY, TY, NP, Qy, Gw, NY among others (see Fig. 1a, Nc-Cow1 row).
Claim 8 is included because the cysteine residues would form bridging moiety.
Claim 30 is included because Sok et al preformed tests under physiological condition, the cow1 HCDR3 knob must with carrier.
Claim 58 is included because the linker is “optional”.
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The reference teachings anticipate the claimed invention.
Claim(s) 1, 2, 4, 6, 8, 11, 18, 57 are rejected under 35 U.S.C. 102a(1) as being anticipated by Vadnais et al. (Current Opinion in Structural Biology 38:62-67 (2016), IDS NPL #31, Submitted 2/17/2023).
Vadnais teaches an antibody that binds an antigen of interest which comprises a knob domain of bovine ultralong CDR-H3 which lacks the stalk domain. See Figure 1B.
The reference teachings anticipate the claimed invention.
Claim(s) 1, 2, 4, 6, 8, 11, 18, 30, 57 are rejected under 35 U.S.C. 102a(1) as being anticipated by Stanfield et al. (Sci Immunol. 1(1):1-21 (2017), IDS NPL #28, Submitted 2/17/2023),.
Stanfield teaches an antibody (Fab E03 knob domain) that binds an antigen of interest which comprises a knob domain of bovine ultralong CDR-H3 which lacks the stalk domain. See figure 7 and capture below - this represents a knob domain without a stalk.
Claim 1 is included because E03 is the knob domain of a bovine ultralong CDR-H3.
Claim 2 is included because the knob domain comprises at least two cysteine residues.
Claim 4 is included because the motif RSCP is at the N-terminal extremity.
Claim 6 is included because E03 is more than 5 amino acids in length and less than 55 amino acids in length.
Claim 8 is included because the cysteine residues would form a bridging moiety.
Claim 11 is included because E03 is fully bovine.
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The reference teachings anticipate the claimed invention.
Claim Rejections - 35 USC § 103
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 following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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 the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, 4, 6, 8, 11, 18, 23, 30, 57, and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Bazirgan et al. (WO2013/106485 A2, IDS #1, Submitted 9/23/2022, hereinafter “Bazirgan”).
Regarding claims 1 and 57, Bazirgan teaches the attachment of a peptide (G-CSF) specifically to a knob domain of a bovine ultralong CDRH3 sequence, and alternatively to a stalk domain of an ultralong CDRH3 sequence (para 0235). This is teaching the use the knob domain or a portion thereof as a separate, isolated domain, with a reasonable expectation of success. Regarding claim 58, which discloses a polypeptide comprising at least two isolated antibody fragments as defined in claim 57 optionally linked together by a linker, Bazirgan teaches a first antibody sequence and a second antibody sequence as well as a first and/or second linker sequence, or combinations thereof (para 0169 and 0170). Regarding claim 2, which further limits the isolated antibody fragment of claim 1 to specific numbers of cysteine residues or disulphide bonds, Bazirgan teaches an ultralong CDR3 which comprises specified numbers of cysteine residues (para 0009). Thus, a person with ordinary skill in the art would find it obvious to specify the cysteine content of an isolated knob domain with a reasonable expectation of success. Claim 4 recites “An isolated antibody fragment according to claim 1, which comprises a (Z1) X1 C X2 motif at its N-terminal extremity, wherein:
Z1 is present or absent, and when Z1 is present, Z1 represents 1 amino acid or 2, 3, 4, or 5 independently selected amino acids; and,
X1 is any amino acid residue; and,
C is cysteine; and,
X2 is an amino acid selected from the list consisting of Proline, Arginine, Histidine, Lysine, Glycine and Serine; and/or
wherein said isolated antibody fragment comprises a (AB)n and/or (BA)n motif, wherein A is any amino acid residue, B is an aromatic amino acid selected from the group consisting of: tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), and wherein n is 1, 2, 3, or 4.” Bazirgan specifically teaches embodiments wherein the ultralong CDR3 further comprises a (XaXb)z motif, wherein Xa is any amino acid residue, Xb is an aromatic amino acid selected from the group consisting of: tyrosine (Y), phenylalanine (F), tryptophan (W), and histidine (H), and wherein z is 1-4 (para 0028). Thus, a person of ordinary skill in the art would find it obvious to use the elected (AB)n motif with a reasonable expectation of success. Regarding claim 6, which further limits the amino acid length of the isolated antibody fragment of claim 57, Bazirgan teaches embodiments of ultralong CDR3 which are 35 amino acids in length or longer, 40 amino acids in length or longer, 45 amino acids in length or longer, 50 amino acids in length or longer, 55 amino acids in length or longer (para 0007). Thus, a person of ordinary skill in the art would find it obvious to specify the amino acid length of an isolated antibody fragment of a ultralong CDR3 with a reasonable expectation of success. Regarding claim 8, which further limits the isolated antibody fragment of claim 57 to further comprising a bridging moiety between two amino acids, Bazirgan teaches an ultralong CDR3 comprising an additional amino acid sequence comprising two to six amino acid residues or more positioned between the VH sequence and the DH sequence (para 0016). Thus, a person of ordinary skill in the art would find it obvious to have a bridging moiety between two amino acids in the isolated antibody fragment of claim 57 with a reasonable expectation of success. Regarding claim 11, which further limits the isolated antibody fragment of claim 57 to being fully bovine, chimeric, or synthetic, Bazirgan teaches antibodies or binding fragments thereof which may be bovine (para 00149), are chimeric (para 0053), and also of a ruminant which is a cow (para 0054 and 0055). Thus, it would be obvious to a person of ordinary skill in the art to have an isolated antibody fragment which is fully bovine, chimeric, or synthetic with a reasonable expectation of success. Claim 18 of the instant application discloses a polypeptide comprising at least one isolated antibody fragment as defined in claim 57. Bazirgan teaches some embodiments being an antibody or antibody fragment thereof comprising (a) a first antibody sequence, wherein at least a portion of the first antibody sequence is derived from a least a portion of an ultralong CDR3; (b) a non-antibody sequence; and (c) optionally, a second antibody sequence, wherein at least a portion of the second antibody sequence is derived from at least a portion of an ultralong CDR3 (para 0146). Thus, a person of ordinary skill in the art would find it obvious to have a polypeptide comprising at least one isolated antibody fragment with a reasonable expectation of success. Claim 23 of the instant application reads on an isolated antibody fragment according to claim 57, or a polypeptide comprising the isolated antibody fragment, wherein said fragment or polypeptide is fused to one or more effector molecules, optionally via a linker. In the art, Bazirgan teaches attachment of G-CSF specifically to the knob domain of bovine ultralong CDRH3. Thus, a person of ordinary skill in the art would find it obvious to fuse effector molecules to a knob domain of bovine ultralong CDRH3 with reasonable expectation of success. Claim 30 discloses a pharmaceutical composition comprising an isolated antibody fragment as defined in claim 1, or a polypeptide comprising the isolated antibody fragment, in combination with one or more of a pharmaceutically acceptable excipient, diluent or carrier. Bazirgan discloses in some embodiments a pharmaceutical composition comprising an antibody or fragment thereof comprising sequence based on or derived from at least a portion of an ultralong CDR3 and a pharmaceutically acceptable excipient (para 00186). Thus, is would be obvious to a person of ordinary skill in the art to make a pharmaceutical composition with a reasonable expectation of success. From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. 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.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Bazirgan in view of Rother et al (Nat Biotechnol 25, 1256–1264 (2007)., hereinafter “Rother”, PTO-892). Claim 14 further limits the isolated antibody fragment of claim 57 to having an antigen of component C5 of the Complement. Bazirgan teaches use of a knob domain peptide, but does not teach the targeting of C5 as an antigen of interest. However, in analogous art, Rother teaches C5 as an attractive target for rational design of a therapeutic complement inhibitor. Thus, a person of ordinary skill in the art could combine the knob domain teaching of Bazirgan with the teaching of Rother to target C5 of the complement as an antigen of interest with a reasonable expectation of success. From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. 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.
Claim 16 and claim 28 are rejected under 35 U.S.C. 103 as being unpatentable over Bazirgan in view of Adams et al. (WO2013/068571 A1, IDS Foreign Patent Reference #17, Submitted 2/17/2023, hereinafter “Adams”). Claim 16 reads on an isolated antibody fragment or polypeptide according to claim 57, wherein the antigen of interest is human serum albumin. Bazirgan teaches use specifically of the knob domain of bovine ultralong CDRH3. In analogous art, Adams teaches albumin binding antibodies (e.g., albumin being targeted as an antigen) to extend in vivo half-life of drugs or proteins. Thus, a person of ordinary skill in the art could combine the knob domain teachings of Bazirgan with the albumin-binding antibody teachings of Adams with a reasonable expectation of success. Claim 28 reads on an isolated antibody fragment or polypeptide according to claim 23, wherein the effector molecule is albumin or a protein comprising an albumin binding domain. Bazirgan teaches use specifically of the knob domain of bovine ultralong CDRH3. In analogous art, Adams teaches albumin or albumin binding domains being used as an effector to extend in vivo half-life of drugs or proteins conjugated thereto (para 0001, line 4-5). Thus, a person of ordinary skill in the art could combine the knob domain teachings of Bazirgan with the albumin teachings of Adams with a reasonable expectation of success. From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. 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.
Claims 1-2, 4, 6, 8, 11, 18, 23, 30 and 57-58 are rejected under 35 U.S.C. 103 as being unpatentable over Sok et al (Nature 548, 108–111 (2017), IDS NPL #1, Submitted 11/11/2024) in view of Bazirgan et al. (WO2013/106485 A2, IDS Foreign Patent Reference #1, Submitted 9/23/2022).
The teachings of Sok et al reference have been discussed, supra.
The reference teachings differ from the claimed invention only in the antibody fragment comprising between 5-55 amino acid length in claim 6, and that the fragment is fused to one or more effector molecules in claim 23.
The teaching of Bazirgan et al have been discussed, supra.
It would have been obvious to those skilled in the art before the effective filing date of the claimed invention to combine the teachings of Sok et al. with the teachings of Bazirgan et al. regarding specified length of amino acid sequence, and attachment of effector molecules for enhancement of physiochemical properties, with a reasonable expectation of success. From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. 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.
Conclusion
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/ALAN ALFANO/Examiner, Art Unit 1641
/MAHER M HADDAD/Primary Examiner, Art Unit 1641