Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Applicant’s 7-21-26 election of Group I, and the species of binding molecule comprising the amino acid sequence of SEQ ID NO: 20, with traverse, is acknowledged.
Applicant traverses the restriction and election of species requirements on several grounds.
With respect to the restriction between Groups I and II, applicant asserts the following: “the Examiner has alleged that the inventions are related as product and process of use and that ‘the process for using the product as claimed can be practiced with another materially different product, e.g., a proliferative disease can be treated with a chemotherapeutic agent or a CAR comprising T-cell.’ Office Action at page 2. Applicant submits that this at most demonstrates theoretical distinctness but does not establish the serious search and examination burden required to sustain restriction. Group Il consists of a single claim, i.e., claim 29, which recites ‘administering to a subject in need thereof an effective amount of the binding molecule of
claim 1.’ Claim 29 therefore incorporates every limitation of elected claim 1, including the
requirements that the binding molecule comprise ‘a first binding domain compris[ing] SEQ
ID NO: 2, 4, or 6’ that ‘binds to serum albumin and is positioned at the N-terminus of a
second binding domain,’ ‘the second binding domain binds to a tumor antigen on a target
cell and is positioned at the N-terminus of a third binding domain,’ and ‘the third binding
domain binds to a T cell CD3 receptor complex.’ Examining claim 29 requires no search
beyond that already necessary for the binding molecule of claim 1. Indeed, the Examiner's
own rejoinder statement confirms this substantial overlap, noting that ‘withdrawn process
claims that include all the limitations of the allowable product/apparatus claims should be
considered for rejoinder.’ Office Action at page 5. This acknowledgment underscores the
absence of any independent search burden for claim 29.”
Applicant's arguments have been considered but have not been found convincing, essentially for the reasons of record as set forth in the Restriction Requirement mailed 4-21-26, as described below.
With respect to applicant’s argument that “Examining claim 29 requires no search
beyond that already necessary for the binding molecule of claim 1,” the examiner points applicant’s attention to Section 3 of the restriction requirement describing why there would be a serious search and examination burden to examine both groups of inventions together, in particular, examining the breadth of method claim 29 which encompasses in its breadth treating any inflammatory disease, infectious or autoimmune disease by administering an effective amount of the binding molecule of claim 1 certainly will “raise different non-prior art issues under 35 U.S.C. 101 and/or 35 U.S.C. 112(a),” for example, which particular second binding domains that bind “a tumor antigen” would be expected to treat any inflammatory disease, infectious or autoimmune disease? At first glance it is not apparent how CEA or CD33 binding could be used to treat any inflammatory disease, infectious or autoimmune disease.
With respect to applicant’s assertion that "the Examiner's own rejoinder statement confirms this substantial overlap, noting that ‘withdrawn process claims that include all the limitations of the allowable product/apparatus claims should be considered for rejoinder,’" this appears to be nothing more than a re-statement of Section 7 of the Restriction Requirement which does not concede a lack of distinctness; rather it merely provide a procedural mechanism to withdraw an otherwise proper restriction requirement once the elected claims are found fully allowable on the merits and in the instance that the non-elected claims require all the limitations of the allowable product claims.
Moreover, with respect to the election-of-species requirement for sequences, applicant further asserts: “the Examiner has alleged that the sequence species are patentably distinct due to ‘different structures and, in turn, different biophysical properties.’ Office Action at page 3. Applicant submits that the recited sequences as set forth in claim 20 all share a single substantial common structural feature, i.e., each is a single polypeptide chain binding molecule having an N-
terminal serum-albumin-binding domain comprising SEQ ID NO: 2, 4, or 6, a second domain
binding a tumor antigen, and a third domain binding the T cell CD3 receptor complex, i.e.,
the shared structure recited by generic claim 1. A search directed to that shared generic
structure necessarily encompasses each species, so no serious search or examination
burden has been shown. Notably, the Examiner acknowledges that ‘[c]urrently, all claims
appear to be generic.’ Office Action at page 3. This confirms that a single generic claim (claim 1) reads on every listed sequence species and further undercuts any alleged search
burden.”
With respect to applicant’s argument that no serious search or examination burden has been shown, as stated in the Restriction Requirement mailed 4-21-26 there is a search and/or examination burden for the patentably distinct species as set forth above because at least the following reason(s) apply: the species require a different field of search (e.g., employing different search queries); the prior art applicable to one species would not likely be applicable to another species; and the species are likely to raise different non-prior art issues under 35 U.S.C. 101 and/or 35 U.S.C. 112, first paragraph. For example, SEQ ID NOs: 8, 12 and 20 each encode binding molecules that recognize different tumor antigens, while SEQ ID NOs: 16, 20, 24, 26, 30 and 34 comprise different albumin binding domains selected from SEQ ID NOs: 2, 4 and 6.
In conclusion, the restriction / election of species requirements set forth 4-21-26 are still deemed proper and are therefore made FINAL.
Claims 1, 4-6, 8, 10, 17, 19, 20, 23-27, 29 and 30 are pending.
Claims 1, 4-6, 8, 10, 17, 19, 20, 23-26, 27 and 30 are under examination as they read on the elected species of single polypeptide chain binding molecule having an overall structure of SEQ ID NO: 20.
Claim 29 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Group, there being no allowable generic or linking claim. Notably, 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)).
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 1, 4, 8, 10, 17, 19, 23-27 and 30 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kufer et al. (20100150918) in view of Hammond et al. (20080044413) and Dennis et al. (20060228364), as evidenced by Baeuerle et al. (Cancer Res 2009;69:4941-4944); Hopp et al. (Protein Engineering, Design & Selection vol. 23 no. 11 pp. 827–834, 2010); Andersen et al. (Recombinant Antibodies For Immunotherapy, Cambridge University Press, Chapter 20, “Extending Antibody Half-Lives With Albumin,” pages 293-309, 2009); Choi et al. (Expert Opinion on Biological Therapy, 11:7, 843-853); Bluemel et al. (Cancer Immunol Immunother (2010) 59:1197–1209) and Molhoj et al., (Molecular Immunology 44 (2007) 1935-1943). (all cited on an IDS).
State of the Art
The instant claims encompass in their breadth embodiments including a single polypeptide chain binding molecule comprising at least three binding domains wherein (a) the first domain is a binding domain which binds to serum albumin; (b) the second domain is a binding domain which binds to a cell surface molecule on a target cell; and (c) the third domain is a binding domain which binds to a T cell CD3 receptor complex, wherein said first domain is a peptide comprising between 10 and 25 amino acids and is further positioned at the N-terminal end of the binding molecule (see claim 10). The claims also encompass embodiments wherein all three of said binding domains bind both human and non-human primate versions of their cognate ligands (see claim 8) and wherein some of the binding domains comprise antibody Vh and Vl chains (see claim 17).
Bispecific single chain antibodies comprising (i) a first binding domain that binds to a cell surface molecule on a target cell, such as a tumor associated antigen, and (ii) a second binding domain that binds to a T cell CD3 receptor complex, wherein said first and second binding domains comprise antibody derived VL and VH chains were well known in the art prior to applicant’s date of invention and had been used to treat a variety of cancers in preclinical and clinical setting.
For example, Baeuerle teaches bispecific T-cell engaging (BiTE) constructs which bind cell surface tumor associated antigens, such as CD19, CD33 or EphA2, and further bind CD3, have been successfully used as cancer therapeutics (see, e.g., page 4941, right col., 1st and 2nd full paragraphs).
A well-recognized feature of the “BiTE” constructs described by Baeuerle is that, because they have a serum half-life of several hours as compared to multiple days or weeks for conventional antibodies, BiTE constructs need to be continuously administered throughout the time period during which they are needed to redirect CD3-expressing T cells to tumor cells expressing the cell surface molecule recognized by the first domain.
For example, Baeuerle teaches tumor antigen:CD3 binding BiTE constructs in clinical use have been administered to patients by continuous intravenous infusion for 4 to 8 weeks using a portable minipump (see page 4944 col. bridging paragraph).
That said Baeuerle continues, “studies in rodents and primates have shown that various BiTE antibodies are also bioavailable after subcutaneous administration (10). Subcutaneous delivery by repeated bolus injection was feasible, as was a continuous subcutaneous delivery by an insulin minipump device. These approaches promise a further improvement of convenience.” (see ibid).
Thus, it was recognized in the prior art that the administration of BiTE constructs could be improved in particular by (i) subcutaneous delivery by repeated bolus injection or by (ii) continuous subcutaneous delivery by an insulin minipump device.
It would be obvious to one of ordinary skill in the art prior to applicant’s date of invention that the former (i) would be preferable to the latter (ii) with respect to patient convenience and in terms of being a far simpler method of delivery in terms of the technical requirements for delivery of the antibody via syringe versus a minipump. However, in order to facilitate intermittent dosing by repeated, subcutaneous bolus injection a BiTE construct with a longer half-life so as to maintain clinically relevant concentrations in the blood for longer periods of time would be desirable so as to minimize the required frequency of injections as much as possible.
In contemplating how one might go about extending the half-life of a BiTE construct, it would be obvious to the ordinarily skilled artisan that the teachings of Hopp provide a relevant example.
Hopp describes how a bispecific CEA, CD3 binding diabodies fused at their C-terminal or at their N-terminal and C-terminal ends to various normal, low and high affinity derivatives of the ABD of streptococcal protein G1 (see Fig. l) have extended serum half-lives and similar abilities to bind CEA or CD3 expressing cells in the presence or absence of HSA (see Table 1), but differ more so in their ability to stimulate IL-2 release from PBMCs in response to CEA expressing target cells in vitro in the presence of albumin, the ABD2 type fusion protein having the least ability to stimulate IL-2 release from PBMCs (see Figs. 2, 6 and the associated text in Results).
Hopp concludes, “…altering the affinity or valency of albumin binding has only minor effects on the half-life of scDb-ABD fusion proteins in mice…Most notably, our results demonstrate that an increased affinity of the ABD does not result in a significant improvement of half-life indicating a limit of half-life extension that can be reached through binding to albumin. Taken together, it becomes evident that even molecules with medium affinity for albumin are appropriate to prolong half-life of therapeutic proteins in accordance with various reports where low-to-medium affinity molecules such as albumin-binding chemicals, peptides and antibody domains were successfully employed to extend plasma half-lives.” (see page 834, last paragraph).
While the skilled artisan would recognize structural similarities between the single-chain, bispecific CD3 and tumor cell surface antigen binding diabody of Hopp, and the BiTE molecules described by Baeurle, there was wide-spread knowledge in the art that, in general, antibody fragments having short half-lives due to their small size could be made more useful for therapeutic purposes by fusing to them to an albumin binding domain (see, e.g., Andersen at pages 300-303).
With the knowledge in the art of BiTE constructs and their means of administration, and of improving the therapeutic potential of antibody fragments by fusing them to an albumin binding domain in mind, please consider the following case of prima facie obviousness:
Kufer teaches BiTE constructs comprising a first domain that binds a cell surface molecule on a target cell, such as a tumor associated antigen on a cancer cell, and further comprising a second domain that binds the T cell CD3 receptor complex, wherein said first and second domains bind their target antigens with cross-species specificity to human and non-chimpanzee primate CD3 and tumor associated antigens. Kufer further teaches pharmaceutical compositions and kits comprising said BiTE constructs (see, e.g., paragraphs 10-16, 117-118, 131, 156-158 and 183). With respect to claims 23-26, Kufer further teaches nucleic acids encoding their BiTE constructs, vectors comprising said nucleic acids, host cells transformed or transfected with said nucleic acids, and processes for expressing their BiTE construct from host cells transformed or transfected with said nucleic acids (see, e.g., paragraphs 132-146; 152-155).
As would be obvious to one of ordinary skill in the art, BiTE constructs with cross-species specificity to human and non-chimpanzee primate CD3 and tumor associated antigens offer many advantages over BiTE molecules, e.g., where one or more of the subunits binds to only human derived CD3 and/or tumor associated antigen (see Kufer paragraphs 8, 10, 16 and 23-29). In sum, these advantages discussed by Kufer are all based on the fact that BiTE constructs with cross-species specificity to human and non-chimpanzee primate CD3 and tumor associated antigens enable one to use the same molecule for therapeutics in humans as was assessed in preclinical non-human primate testing.
In addition, Kufer teaches their cross-species specific BiTE (cssBiTE) constructs can be administered to a patient via continuous infusion using a small pump system worn by the patient for metering the influx of therapeutic agent into the body of the patient, or via a pump system for subcutaneous administration, said pump including a needle or a cannula for penetrating the skin of a patient and delivering a suitable amount of the composition into the patient's body (see paragraphs 158-159).
Furthermore, Kufer describes an open-label, multi-center phase I interpatient dose-escalation trial for the treatment of patients with B-cell Non-Hodgkin-Lymphoma (B-NHL) using a conventional, non-cssBiTE that binds human CD19 and CD3. In this clinical trial patients received the conventional BiTE by continuous intravenous infusion with a portable minipump system over four weeks at constant flow rate (i.e. dose level). Patients were hospitalized during
the first two weeks of treatment before they were released from the hospital and continued treatment at home. Patients without evidence of disease progression after four weeks were offered to continue treatment for further four weeks (see Section 20 beginning on page 42 including esp. paragraph 541.
Kufer does not explicitly teach BiTE constructs having three domains wherein the first domain binds serum albumin and is positioned N-terminal to the second binding domain which binds to a tumor antigen, which is, in turn, positioned N-terminal to the third binding domain which binds to a T cell CD3 receptor complex, or variants thereof having a C-terminal His-tag.
Given the teachings of Kufer and the ordinary creativity and knowledge of one skilled in the art it would have been obvious that while a cssBiTE would greatly simplify and accelerate the transition from preclinical animal testing to the treatment of human patients, therapeutic application of the cssBiTE could be further improved if it could be maintained at clinically relevant plasma concentrations without having to resort to inconvenient and technically complex continuous infusion for 8 weeks. In this regard, it was well known in the art (as described above) that antibody fragments with short in vivo half-lives can be modified by fusion to a peptidic moiety that binds albumin.
Moreover, one of ordinary skill in the art would have had a reasonable expectation of successfully modifying a molecule like the cssBiTE of Kufer by fusion to a peptidic moiety that binds albumin in view of the teachings of Hammond:
Hammond teaches a bispecific T-cell engaging (BiTE) construct comprising three binding domains comprised in a single polypeptide chain: one domain comprising Vh and Vl chains and being capable of binding a cell surface molecule overexpressed in a number of different tumor types, such as EphA2; a second domain comprising Vh and Vl chains and being capable of binding the T cell CD3 receptor complex, and a third domain being a peptide or polypeptide capable of binding a large variety of other molecules (see, e.g., paragraphs 5, 150-154, 193, 194, 196 and 203).
With respect to the order of the various domains within the BiTE construct Hammond teaches all arrangements are possible noting "[i]t is important, however, that the VH and VL domains are arranged so that the antigen binding domain can properly fold to recognize and bind antigen;” moreover, Hammond demonstrates BiTE constructs having different Vh and Vl domain arrangements have different effects on the ability of the fusion proteins to direct CD3+ T cells to lyse EphA2 expressing tumor cells (see paragraphs 146-154 and 436-488).
With respect to what type of ABD should be fused to the cssBiTE molecule of Kufer, while the teachings of Hopp provide an example wherein an ABD derived from streptococcal protein G was used, the skilled artisan would also have been aware of peptide-sized albumin binding moieties as well.
For example, Dennis teaches the half-life of tumor targeting antibody fragments such as scFv can be prolonged by fusing a domain capable of binding to serum albumin to either the N-terminus or C- terminus (see, e.g., pars. 14-23, 73, 74, 93, 194 and 232; Example 1 and claims 25 and 37). One of the albumin binding peptides featured by Dennis has the sequence Asp-Xaa-Cys-Leu-Pro-Xaa-Trp-Gly-Cys-Leu-Trp (see pars. 18 and 69, Dennis SEQ ID NO: 4).
As described in MPEP § 2143, prima facie obviousness can be established based upon a teaching, suggestion, or motivation in the prior art, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, that would have led one of ordinary skill to modify the prior art teachings or to combine the prior art teachings to arrive at the claimed invention.
That said, implicit motivation to combine prior art references exists if the claimed improvement is technology-independent and the combination results in a product or process that is more desirable, as well as if the suggestion to combine may be gleaned from the prior art as a whole. Motivation to combine exists in such circumstance, even in the absence of a suggestion in the references themselves, since the desire to enhance commercial opportunities by improving products or processes is universal and even common-sensical, and in such a situation the proper question is whether the ordinary artisan possesses knowledge and skills rendering him or her capable of combining the prior art references. See, Dystar Textilfarben GmbH & Co., Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641 at pp. 1651 and 1653 (Fed. Cir. 2006), citing Pro-Mold & Tool Inc., v. Great Lakes Plastics, Inc., 75 F.3d 1568, 37 USPQ2d 1626 (Fed. Cir. 1996); see also Leapfrog Enter., Inc. v. Fisher-Price, Inc., 485 F.3d 1157, 1161 (Fed. Cir. 2007).
Given the reference teachings and the knowledge in the art it would have been prima facie obvious to one of ordinary skill in the art to combine elements of the reference teachings according to known methods to yield predictable results. It would have been prima facie obvious to modify the cssBiTE described by Kufer by attaching a peptidic albumin binding moiety.
Such a modification would obviously be most easily accomplished using recombinant DNA techniques (well-known to one of ordinarily skilled artisan as of applicant’s earliest filing date); said techniques based on nucleic acids encoding said cssBiTE and said peptidic albumin binding moiety, to create a nucleic acid encoding a cssBiTE-peptidic albumin binding moiety fusion protein.
With such a nucleic acid in hand, it further would have been obvious to one of ordinary skill in the art to create expression vectors comprising said nucleic acid encoding a cssBiTE-peptidic albumin binding moiety fusion protein which could, in turn, be used to transform or transfect a host cell for the purpose of, e.g., culturing said host cells to a level sufficient to express substantial amounts of said nucleic acid encoded, cssBiTE-peptidic albumin binding moiety fusion protein.
One reasons it would have been obvious to one of ordinary skill in the art to take such steps prior to applicant’s earliest filed application was because the small size of unmodified BiTE molecules meant they must be continuously infused for an extended period of time (8 weeks) to maintain sufficient levels in the body for treatment; however, as would have been obvious to one of ordinary skill in the art at that time, modification of the cssBiTE to impart albumin binding would allow the BiTE to have a longer half-life thereby facilitating intermittent rather than continuous dosing.
As would have been obvious to one of ordinary skill in the art, the ability to deliver a BiTE construct by intermittent rather than continuous dosing would facilitate long term maintenance dosing for those patients at risk of relapse, as well as eliminate the need for an insulin-like minipump to deliver the BiTE construct, which obviously poses many inconveniences for patients such as the necessity to be continuously linked to a device that would likely be sensitive to environmental challenges like water immersion or temperature extremes.
This obvious idea of improving the half-life of a cssBiTE by fusing a peptidic albumin binding moiety to the BiTE is not only consistent with the teachings of Kufer and Hammond as they would be viewed through the knowledge of one of ordinary skill in the art, but also consistent with the general knowledge in the art, as described, e.g., by Choi which concludes:
“…Given that current clinical protocols for bispecific therapeutics inconveniently require continuous infusion over several weeks, as the field continues to mature, priorities will converge on molecular modifications that are designed to enhance half-life and maintenance at clinically relevant plasma concentrations….” (see page 850, col. bridging paragraph).
With respect to the particular ABD to be attached to the BiTE, a reason the skilled artisan would have been drawn to the albumin-binding peptides of Dennis are their relatively smaller size.
A smaller sized albumin-binding domain would have been desirable to the ordinarily skilled artisan because one influence on the potency of BiTE constructs is the distance between the target cell and T cell membranes which is influenced by the overall size of the BiTE construct (see Discussion of Bluemel).
Thus, it would have been obvious to one of ordinary skill in the art that fusion to a relatively small albumin-binding peptide should add less to the structure of the BiTE construct than fusion to a larger polypeptide-based albumin binding moiety, which could help by providing greater flexibility when engineering BiTEs having various tumor antigen binding specificities.
With respect to which particular albumin-binding peptide of Dennis should be used to modify the cssBITE, Dennis teaches a number of peptides comprising the core sequence Asp-Xaa-Cys-Leu-Pro-Xaa-Trp-Gly-Cys-Leu-Trp bind albumin with relatively high affinity (see, e.g., paragraphs 168, 173 and the sequences of Table 9). For example, the "SA2l" peptide depicted in Table 8 has the highest affinity for human serum albumin and good cross-reactivity with rabbit, rat and mouse serum albumins (see paragraphs 170-172 and Table 8).
Given the ability of the SA21 peptide displayed in Table 8 of Dennis to bind most strongly to human serum albumin (as compared to the other ABDs profiled in Table 8), and with even greater affinity to rabbit, rat and mouse albumins, it would have been obvious to one of ordinary skill in the art that this particular peptide would be a good choice as the ABD to attach to a BiTE molecule because it would allow for experimentation in a variety of preclinical model systems as well as for therapeutic administration to human patients.
Indeed, given that this peptide binds human, rabbit, rat and mouse albumins with high affinity it would be reasonable for the skilled artisan to expect this peptide to also bind non-human primate albumin since such albumins would have been well known to the ordinarily skilled artisan to be yet even more similar to human albumin than the rabbit, rat or mouse homologs (see the sequences disclosed in IDS citation numbers C1, C41, C73 and C78 and the attached alignment of said cited sequences).
In terms of the placement of the albumin binding peptide relative to the other domains of the cssBiTE construct, given the teachings of Hammond as well as Dennis it would have been obvious to the ordinarily skilled artisan that one cannot predict, a priori, how the placement of an albumin binding peptide at either the N-terminus or C-terminus of a BiTE construct may affect the ability of the BiTE to be properly translated and folded; or its ability to bind tumor antigen, CD3 antigen or albumin; or its ability to mediate synapse formation between a T cell and a target cell2.
Thus, it would have been obvious to one of ordinary skill in the art contemplating fusing an albumin binding peptide (ABP) to a BiTE construct as of applicant’s date of invention that BiTE constructs having all four arrangements of albumin binding peptide (i.e., (i) ABP fused N-terminal to a first BiTE domain which binds a cell surface molecule on a target cell, (ii) ABP fused N-terminal to a first BiTE domain which binds a T cell CD3 receptor complex, (iii) ABP fused C-terminal to a second BiTE domain which binds a cell surface molecule on a target cell or (iv) ABP fused C-terminal to a second BiTE domain which binds a T cell CD3 receptor complex) should be prepared and tested to determine which fusion protein has the optimum ability to be properly translated and folded; to bind tumor antigen, CD3 antigen and albumin; and to mediate synapse formation between a T cell and a target cell.
One of ordinary skill in the art would have had a reasonable expectation of successfully doing so
in view of the teachings of Hammond showing the routine re-arrangement of BiTE antigen binding domains (see, e.g., paragraphs 151, 440, 465, 484, 611, 616) to optimize antigen binding affinity (see, e.g., paragraph 0478), antibody production (see, e.g., paragraph 0484) and ability to mediate redirected lysis of antigen-positive target cells (see, e.g., paragraph 0487).
When taken together and considered in the context of the ordinary knowledge in the art as of applicant’s date of invention, the teachings of Kufer and Hammond would have given the ordinarily skilled artisan a reasonable expectation that fusion of a peptide-based ABD, such as the SA21 peptide of Dennis, to the N- or C-terminus of a cross-species specific BiTE will yield a serum stabilized fusion construct with acceptable ability to mediate T cell redirected killing of antigen expressing target cells. Moreover, given the reference teachings and the knowledge in the therapeutic BiTE art, one of ordinary skill in the art would have been motivated to make single polypeptide chain binding molecules according to the instant claims, pharmaceutical compositions thereof and kits thereof.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at 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.
Claim 5 and 6 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kufer et al. (20100150918) in view of Hammond et al. (20080044413) and Dennis et al. (20060228364), as evidenced by Baeuerle et al. (Cancer Res 2009;69:4941-4944); Hopp et al. (Protein Engineering, Design & Selection vol. 23 no. 11 pp. 827–834, 2010); Andersen et al. (Recombinant Antibodies For Immunotherapy, Cambridge University Press, Chapter 20, “Extending Antibody Half-Lives With Albumin,” pages 293-309, 2009); Choi et al. (Expert Opinion on Biological Therapy, 11:7, 843-853); Bluemel et al. (Cancer Immunol Immunother (2010) 59:1197–1209) and Molhoj et al., Molecular Immunology 44 (2007) 1935-1943 as applied to claims 1, 4, 8, 10, 17, 19, 23-27 and 30 above, and further for the reasons given below.
The reference teachings of Kufer, Hammond and Dennis as they would be understood in the context of the knowledge in the art as exemplified by Baeuerle, Hopp, Andersen, Choi, Bluemel and Molhoj are given above.
The instant claims further specify the single polypeptide chain binding molecule comprising at least three binding domains wherein the first binding domain that is capable of binding to serum albumin and is positioned N-terminal to the second binding domain…, “comprises one or more additional heterologous polypeptide(s)” (claim 5), such as a His-tag (claim 6).
While not elaborated upon in the previous rejection, in one particular embodiment Hammond further describes a BiTE construct comprising three domains where the third domain is a peptide capable of binding to a ligand such as a hexa-histidine tag (His) capable of binding to nickel-NTA or an anti-His antibody, or a hemagglutinin tag (HA) capable of binding an anti-HA antibody (paragraph 196). Hammond further describes and exemplifies several EphA2-BiTE constructs comprising a His tag positioned at their C-terminus (see Figs. 3, 14B, paragraphs 0091, 0102, 0441, 0468, 0477, 0500 and 0509), and none of these working examples teach that a C-terminally appended hexa-his tag adversely affects BiTE function.
As described in the previous rejection, given the reference teachings it would have been obvious to one of ordinary skill in the art that the skilled artisan cannot, a priori, predict how the placement of an albumin binding peptide at either the N-terminus or C-terminus of a BiTE construct may affect the ability of the BiTE to be properly translated and folded; or its ability to bind tumor antigen, CD3 antigen or albumin; or its ability to mediate synapse formation between a T cell and a target cell. At the same time, the skilled artisan would expect that some BiTE constructs may be superior with the ABD fused to their N-terminus as opposed to C-terminally fused. In such an instance, it would have been obvious to the ordinarily skilled artisan to append a His-tag to the C-terminus of an ABD-BiTE with a reasonable expectation of success in view of the teachings of Hammond described above. One of ordinary skill in the art would have been motivated to so for a variety of reasons, e.g., to facilitate purification or detection of said N-ABD-BiTE-His-C.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at 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.
Claim 20 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kufer et al. (20100150918) in view of Hammond et al. (20080044413) and Dennis et al. (20060228364), as evidenced by Baeuerle et al. (Cancer Res 2009;69:4941-4944); Hopp et al. (Protein Engineering, Design & Selection vol. 23 no. 11 pp. 827–834, 2010); Andersen et al. (Recombinant Antibodies For Immunotherapy, Cambridge University Press, Chapter 20, “Extending Antibody Half-Lives With Albumin,” pages 293-309, 2009); Choi et al. (Expert Opinion on Biological Therapy, 11:7, 843-853, 2011); Bluemel et al. (Cancer Immunol Immunother (2010) 59:1197–1209) and Molhoj et al. (Molecular Immunology 44 (2007), pages 1935-1943) as applied to claims 1, 4, 8, 10, 17, 19, 23-27 and 30 above, and further in view of Hammond (WO2013012414, hereinafter Hammond #2) as evidenced by Lutterbuse et al. (WO2007071426), Traunecker et al. (The EMBO Journal vol. 10 no. 12 pp. 3655 - 3659, 1991), Jacobs et al. (Cancer Immunol Immunother (1997) 44: 257 –264) and Tunnacliffe et al. (Int Immunol. 1989;1(5):546-50). (all cited on an IDS).
The reference teachings of Kufer, Hammond and Dennis as they would be understood in the context of the knowledge art as exemplified by Baeuerle, Hopp, Andersen, Choi, Bluemel and Molhoj are given above.
However, the teaches of Kufer etc. fail to render obvious the binding molecule of claim 1 that comprises SEQ ID NO: 20.
Kufer further teaches how bispecific antibodies comprising their particular, context-independent CD3 binding domain are associated with less T cell redistribution during the starting phase of treatment resulting in a better safety profile compared to conventional CD3 binding molecules known in the art (see, e.g., paragraphs 13). As described by Kufer at paragraph 11, the “context-independence of the CD3 epitope provided in this invention corresponds to the first 27 N-terminal amino acids of CD3 epsilon,” which “does not lead to a change or modification of the
conformation, sequence, or structure surrounding the antigenic determinant or epitope.” By contrast, “the CD3 epitope recognized by a conventional CD3 binding molecule (e.g. as
disclosed in WO 99/54440 or WO 04/106380) is localized on the CD3 epsilon chain C-terminal to the N-terminal 1-27 amino acids of the context-independent epitope, where it only takes the correct conformation if it is embedded within the rest of the epsilon chain and held in the right position by heterodimerization of the epsilon chain with either the CD3 gamma or delta chain.”
Hammond #2 describes bispecific antibodies comprising a CEA binding domain and a CD3 binding domain, wherein the CD3 binding domain is based on the CD3 binding domain disclosed in “WO2007/071426” (see page 15, 1st and 2nd full paragraph of Hammond #2).
As evidenced by the teachings of ‘426 at page 50, Example 2, their particular anti-CD3 binding domain comes from an antibody previously described in “WO 2005/040220.” As described at page 12, 1st full paragraph of the ‘220, their anti-CD3 antibody was derived from the anti-CD3 antibody of Traunecker et al. (1991), known as the “TR66” anti-CD3 antibody in the prior art. The TR66 antibody was believed to recognize the same or an epitope overlapping the epitope of, e.g., the anti-CD3 antibody known as “OKT3” (see Jacobs et al. (1997), at page 259, left col., last paragraph and at page 262, 1st full paragraph; Tunnacliffe et al. (1989), at page 549, 1st full paragraph).
Given the teachings of Kufer concerning the advantages of making bispecific anti-tumor antibodies comprising their particular, context-independent CD3 binding domain, as opposed to a CD3 binding domain from a conventional antibody such as the TR66 anti-CD3 antibody, it would have been obvious to the ordinarily skilled artisan to replace the conventional CD3-binding domain of the Hammond #2 bispecific antibody (said CD3-binding domain known by the ordinarily skilled artisan to be based on the TR66 antibody as described above) with a context-independent CD3-binding domain from Kufer. For example, it would have been obvious to one of ordinary skill in the art to replace the CD3-binding domain of Hammond #2 SEQ ID NOs: 46 or 52 with any one of the H2C, F12Q or I2C CD3-binding domains described in Kufer paragraph 0880, although a reason the ordinarily skilled artisan would have been drawn to the I2C CD3-binding domain in particular is because this domain was featured in the many of Kufer’s working examples, e.g., in Example 35 describing bispecific single chain antibody constructs directed to human and non-chimpanzee primate CD3 and to Tumor Specific Epitopes of Muc-1, wherein paragraph 0833 describes how “[s]ingle clones were then analyzed for favourable properties and amino acid sequence. Muc-1 specific scFvs were converted into recombinant bispecific single chain antibodies by joining them via a Gly4Ser1-linker with the CD3 specific scFv I2C (SEQ ID 185)…” Similarly, additional working examples of Kufer focus on use of the I2C CD3-binding domain containing tumor-antigen binding antibodies in paragraphs 0948 and 0981.
Given the above it would have been obvious to one of ordinary skill in the art, and one of ordinary skill in the art would have been motivated to substitute the I2C CD3 binding domain of Kufer SEQ ID NO: 185 for the CD3-binding domain found, e.g., in the Hammond #2 bispecific antibodies of SEQ ID NOs: 46 and 52.
Moreover, further given the teachings of Hammond and Dennis as they would be understood in the context of the knowledge in the art, it would have been obvious to the ordinarily skilled artisan to append an ABD, such as the SA21 ABD of Dennis, to the N-terminus or the C-terminus of said bispecific antibody.
One of ordinary skill in the art would have been motivated to do so because, given the teachings of Hammond, it would have been obvious to the ordinarily skilled artisan that one cannot predict, a priori, how the placement of an albumin binding peptide at either the N-terminus or C-terminus of a BiTE construct may affect the ability of the BiTE to be properly translated and folded; or its ability to bind tumor antigen, CD3 antigen or albumin; or its ability to mediate synapse formation between a T cell and a target cell.
Even without being able to predict which attachment point for the albumin binding domain would be optimum, the skilled artisan would have a reasonable expectation that attachment of the ABD to one terminus or the other will yield a molecule suitable for therapeutic application.
Moreover, insofar as some BiTE constructs may be superior with the ABD fused to their N-terminus as opposed to C-terminally fused, it would have been obvious to the ordinarily skilled artisan to append a His-tag to the C-terminus of an ABD-BiTE with a reasonable expectation of success in view of the teachings of Hammond as applied to claims 4 and 5 above. One of ordinary skill in the art would have been motivated to so for a variety of reasons, e.g., to facilitate purification or detection of said bispecific antibody.
In making such an N-ABD-BiTE-His-C, the skilled artisan would produce the polypeptide of SEQ ID NO: 20. Thus, in view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at 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.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1, 4-6, 8, 10, 17 and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 8 of U.S. Patent No. 12441796, cited herewith.
Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claim recites SEQ ID NOs: 1490, 1547 and 1554 which comprise the first and third binding domains of elected SEQ ID NO: 20 as shown below:
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Note that in searching for elected SEQ ID NO: 20 reference SEQ ID NOs: 1490, 1547 and 1554 shown above were identified by virtue of their alignment to the albumin binding domain of SEQ ID NO: 20 (SEQ ID NO: 6) and with the CD3-binding portion of SEQ ID NO: 20. Thus, even though these reference SEQ ID NOs: are not identical to SEQ ID NO: 20, they encompass elements of SEQ ID NO: 20 that are generically recited in reference claims 1, 4-6, 8, 10, 17 and 19.
Claims 1, 4-6, 8, 10, 17, 19 and 21 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 6 of U.S. Patent No. 10933132, cited herewith.
Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claim recites SEQ ID NOs: 215 and 221 which comprise the first and third binding domains of elected SEQ ID NO: 20 as shown below:
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Note that in searching for elected SEQ ID NO: 20 reference SEQ ID NOs: 215 and 221 shown above were identified by virtue of their alignment to the albumin binding domain of SEQ ID NO: 20 (SEQ ID NO: 6) and with the CD3-binding portion of SEQ ID NO: 20. Thus, even though these reference SEQ ID NOs: are not identical to SEQ ID NO: 20, they encompass elements of SEQ ID NO: 20 that are generically recited in reference claims 1, 4-6, 8, 10, 17, 19 and 21.
No claims are allowed.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
1 where “ABD” = wild type streptococcal protein G ABD fused to the C-terminus of the bispecific diabody; “ABD-L” = low affinity derivative of streptococcal protein G fused to the C-terminus of the bispecific diabody; “ABD-H” = high affinity derivative of streptococcal protein G fused to the C-terminus of the bispecific diabody and “ABD2" = ABD fused to both the N- and C-terminus of the bispecific diabody.
2 See also Molhoj at page 1942, left col., last full paragraph, which describes how the cell binding domains of BiTE constructs must have sufficient rotational freedom, bending and kinking ability so as to simultaneously bind antigens on separate cell surfaces - CD3 on one cell and target antigen on another in such a way that induces the formation of a synaptic complex.
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