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 7-3-25 elections of the invention of Group I, without traverse, and further election of the species of invention wherein the first binding domain capable of binding to a cell surface molecule on a target cell is “a binding domain which binds to a tumor antigen”; and wherein the species of third binding domain capable of binding to serum albumin is “derived from a CDR of a single domain antibody,” also without traverse, are acknowledged.
It is noted that applicant indicates in their remarks that, inter alia, claims 7 and 16 encompass the elected invention. However, claims 7 and 16 are drawn to binding molecules wherein the third binding domain comprises either SEQ ID NO: 102, or comprises the albumin binding domain of SA08, SA21 and SA25, and none of these albumin binding domains are derived from a CDR of a single domain antibody. Rather, these albumin binding domains were all derived from random peptide display as described in Example 1 of Dennis et al. 2006/0228364 (cited on an IDS).
Claims 1-16, 21, 23 and 24 are pending.
Claims 1-16, 21 and 24 are under examination as they read on the species of invention wherein the first binding domain capable of binding to a cell surface molecule on a target cell is “a binding domain which binds to a tumor antigen”; and wherein the species of third binding domain capable of binding to serum albumin is “derived from a CDR of a single domain antibody.”
Claims 7, 16 and 23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group or species of invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7-3-25.
Claims 1-12, 14-16, 21 and 24 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 Revets et al. (20080267949), 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); Stamova et al. (Molecular Immunology 49 (2011) 474– 482); Vosjan et al. (Mol Cancer Ther. 2012 Apr;11(4):1017-25 and Supplementary materials pages 1-2, Epub 2012 Feb 7, cited herewith); Humphreys (20100239582), Choi et al. (Expert Opinion on Biological Therapy, 11:7, 843-853) and “Human Albumin,” Transfus Med Hemother 2009;36:399–407 (all refs cited on an IDS unless otherwise noted).
State of the Art
Pending claim 1 is drawn to a binding molecule comprising at least three binding domains comprised in at least one polypeptide chain, wherein (a) the first domain is a binding domain which is capable of binding to a cell surface molecule on a target cell; and (b) the second domain is a binding domain which is capable of binding to the T cell CD3 receptor complex; and (c) the third domain is a binding domain which is capable of binding to serum albumin, wherein said third domain is positioned at the C- terminus of said second domain.
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 the EphA2, and further bind CD3, and had been successfully used as cancer therapeutics (see, e.g., page 4941, right col., 1st and 2nd full paragraphs).
A feature of the “BiTE” constructs described by Baeuerle well-known to one of ordinary skill in the prior art 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 taught tumor antigen:CD3 binding BiTE constructs in clinical use at that time were 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 administration of BiTE constructs could be improved 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 would be preferable to the latter with respect to patient convenience and in terms of being a far simpler method of delivery (syringe versus minipump). However, in order to facilitate intermittent dosing by repeated, subcutaneous bolus injection, a BiTE construct with a longer half-life 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 one relevant example.
Hopp describes a molecule which comprises, in a single-chain, antibody variable domains joined by linkers wherein the variable domains form two antigen bindings sites, one that binds CD3 and the other which binds CEA. This molecule of Hopp, referred to as a “single-chain diabody,” has a molecular weight (≈ 55kDa) and an in vivo t1/2 (≈ 5 hours), which the skilled artisan would recognize to be nearly identical to the MW and in vivo t1/2 of a BiTE construct. Hopp goes on to teach a method for extending the half-life of their single-chain diabody by fusing to its C-terminus, or by fusing to both termini, a 56 amino acid albumin-binding domain (ABD) from streptococcal protein G (see Introduction and Fig. 1A).
Hopp describes how a bispecific CEA, CD3 binding diabody fused to various derivatives of the ABD of streptococcal protein G (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) have extended serum half-lives, normal abilities to bind CEA or CD3 expressing cells in the presence of albumin, and varying abilities to stimulate IL-2 release from PBMCs in response to CEA expressing target cells in vitro in the presence of albumin (see Table IV, Fig. 2, Fig. 6 and 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).
The ordinarily skilled artisan would appreciate the strong structural similarities between the single-chain, bispecific diabody of Hopp and the BiTE molecules described by Baeurle (see, e.g., Stamova showing a single-chain, bispecific diabody in Fig. 1A as compared to a single-chain, bispecific tandem scFv in Fig. 4A, and describing such molecules at page 475, left col., 1st full paragraph).
The teachings of Vosjan provide yet another example of the knowledge in the prior art of extending the plasma half-life of an immunoglobulin by fusion to an albumin binding domain. In particular, Vosjan teaches a hepatocyte growth factor (HGF) binding "nanobody™,” which is an immunogloublin fragment comprised of the variable domain of a heavy chain only, can be improved for therapeutic applications by fusion to an albumin-binding nanobody designated “Alb8” (see Abstract; page 1020, col. bridging paragraph; Supplementary materials at page 2).
Similar to Vosjan, Humphreys teaches antibody Fab fragments comprising a first specificity to an antigen of interest, such as CD3 or a tumor-associated antigen like CEA, fused to a single domain antibody having specificity for albumin as means to extend their in vivo serum half-life (see, e.g., paragraphs 0001-0012).
While Humphreys exemplifies the fusion of a single domain antibody having specificity for albumin to a Fab (see Figs. 1 and 2; Examples 4-7), Humphreys teaches albumin binding single domain antibodies can be fused to “any suitable antibody format” at paragraph 0092 (emphasis added):
“It will be appreciated that such albumin binding antibodies, in particular single domain antibodies may be conjugated to any other antibody or protein or other molecule, as desired or used in any other suitable context. In one example the single domain antibodies dAbHl, dAbLl,
dAbH2, dAbL2 as described above and shown in FIG. 5 ( a-d) may be incorporated into any suitable antibody format or used as single domain antibodies in any suitable context, such as a fusion or conjugate.”
According to Humphreys, “Typically the N-terminus of the single domain antibody
will be fused to the C-terminus of the heavy or light chain of the Fab or Fab' fragment, directly or via a linker…” (see paragraph 58).
Given the teachings described above, it would be obvious to the ordinarily skilled artisan that antibody fragments having short half-lives due to their small size – such as single-chain bispecific diabodies and BiTE molecules – could be made more useful for therapeutic purposes by fusing to them an albumin binding domain.
With the above knowledge in the art of BiTE constructs and their means of administration, and cognizant of the obviousness of improving the therapeutic potential of antibody fragments by fusing them to an albumin binding domain in mind, please consider the following prima facie case of 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, pharmaceutical compositions and kits thereof (see, e.g., paragraphs 10-16, 117-118, 131, 156-158 and 183). 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 as well as tumor associated antigens enable one to use the same molecule for therapeutics in humans as was assessed in preclinical animal testing.
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 an additional four weeks (see Section 20 beginning on page 42 including esp. paragraph 541).
Kufer does not explicitly teach BiTE constructs having three domains arranged N- to C- terminus where the first domain is a binding domain which is capable of binding to a cell surface molecule on a target cell, the second domain is a binding domain which is capable of binding to the T cell CD3 receptor complex and the third domain is a binding domain which is capable of binding to serum albumin, wherein said third domain is positioned at the C-terminus of said second domain (claim 1) and wherein said third domain is derived from the CDR of a single domain antibody which is capable of binding to serum albumin (species under examination), and further wherein all three of said domains can bind human and non-human primate target antigens (claim 4).
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 prior art (as described above) that antibody fragments with short in vivo half-lives can be modified by fusion to an albumin binding moiety. Additionally, as described above the ordinarily skilled artisan would appreciate the strong structural similarities between the single-chain, bispecific diabody of Hopp and the BiTE molecules described by Baeurle (see, e.g., Stamova showing a single-chain, bispecific diabody in Fig. 1A as compared to a single-chain, bispecific tandem scFv in Fig. 4A and describing such molecules at page 475, left col., 1st full paragraph).
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 C-terminally positioned albumin binding moiety 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 on a target cell 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 150-154, 193, 194, 196 and 203).
With respect to the order of the Vh and Vl 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).
In one particular embodiment described in paragraph 196 Hammond describes a BiTE construct comprising three domains where the third domain is a peptide capable of binding to a ligand, e.g., a hexa-histidine tag (His) capable of binding to nickel-NTA, or a hemagglutinin tag (HA) capable of binding an anti-HA antibody.
Hammond exemplifies several EphA2-BiTE constructs comprising a His tag positioned at their C-terminus and demonstrates strong binding to CD3 and EphA2 (see Fig. 9, cCD3-1 and EA2 containing EphA2-BiTEs, noting that for some constructs the His tag is attached to the C-terminus of the EphA2 binding domain (EA2) while for other constructs the His tag is attached to the C-terminus of the CD3 binding domain (cCD3-1) as described in paragraph 468).
Hammond further exemplifies strong binding to CD3 and EphA2 with several alternative EphA2-BiTE constructs comprising a His tag positioned at their C-terminus, again in some constructs the His tag is attached to the C-terminus of the EphA2 binding domain (EA2) while for other constructs the His tag is attached to the C-terminus of the CD3 binding domain (deimmunized anti-CD3)(see paragraphs 476-479 and associated Table).
Thus, consistent with the teachings of Hammond and with the knowledge in the art described above, 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 C-terminally positioned albumin binding moiety.
With respect to what type of albumin-binding moiety could be C-terminally fused to the cssBiTE molecule of Kufer, while the teachings of Hopp, Vosjan and Humphreys represent various possibilities, the skilled artisan would have further been aware of the teachings of Revets which describes certain advantages associated with albumin binding peptides derived from the CDR of a single domain antibody.
In particular Revets described how, due to its small size, such a peptide may be easier to link and/or to express as part of a fusion protein; that fusion to a small peptide may yield superior solubility and/or stability; and that fusion to a small peptide may cause less steric hindrance or other undesired interactions with the fusion partner (see paragraphs 12, 313 and 365).
An additional reason the ordinarily skilled artisan would have been motivated to use an albumin binding peptide derived from the CDR of a single domain antibody as described by Revets is because the albumin binding peptides of Revets were disclosed to bind both human and cynomolgus albumin (see, e.g., Fig. 6, Examples 5 and 10), and, as described by Kufer, the ordinarily skilled artisan would understand that such cross-species specificity is advantageous for preclinical testing in non-human primate species.
As set forth 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 a person of ordinary skill in the art to combine elements of the reference teachings according to known methods to yield predictable results. It particular, it would have been prima facie obvious to modify the cssBiTE described by Kufer by C-terminal attachment of the albumin binding peptide of Revets. One reasons this is so is because the small size of unmodified BiTE molecules means 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 be obvious to one of ordinary skill in the art, modification of the cssBiTE with an albumin binding peptide would allow the BiTE to have a longer half-life thereby facilitating intermittent rather than continuous dosing.
As would be further 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 binding domain derived for the CDR of an albumin-binding single domain albumin to the BiTE is not only consistent with the teachings of Kufer and Revets 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).
In terms of the placement of the albumin binding peptide relative to the other domains of the cssBiTE construct, while the teachings of Hopp, Humphreys and Hammond all suggest that the albumin binding domain can potentially be joined to the N-terminus or the C-terminus of a given polypeptide, each of these references suggest C-terminal fusion of the albumin binding domain may be preferred.
Thus, consistent with the teachings of Hammond, Revets and the knowledge in the prior art described above, one of ordinary skill in the art would have had a reasonable expectation of successfully modifying a polypeptide like the cssBiTE of Kufer by fusing an albumin binding peptide to the C-terminus.
One of ordinary skill in the art would have had a reasonable expectation of successfully doing so because BiTE constructs modified by the C-terminal addition of a His tag to either the EphA2-binding or the CD3-binding scFv of the BiTE retain strong binding to CD3 and EphA2 as described by Hammond. Thus, in at least one example addition of a peptide to the C-terminus of a BiTE did not substantially alter its ability to bind target cell antigen or CD3.
Moreover, as taught by Hopp fusion of a chemically and thermally stable 56 amino acid ABD from streptococcal protein G to the C-terminus of a single chain bispecific diabody (which is structurally analogous to the BiTE of Kufer, see the teachings of Stamova described above) was well tolerated with respect to its ability to bind the tumor antigen CEA and CD3, with only a modest decrease in the ability of the single chain bispecific diabody to mediate target cell dependent IL-2 release from PBMC in vitro.
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, Hammond and Revets would have given the ordinarily skilled artisan a reasonable expectation that a BiTE comprising, from N- to C-terminus, a first binding domain that is capable of binding to a target cell surface molecule, a second binding domain that is capable of binding to the CD3 receptor complex and a third albumin-binding domain which is derived from the CDR of a single domain antibody will yield a serum stabilized fusion construct with acceptable ability to mediate T cell redirected killing of antigen expressing target cells.
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.
With respect to the limitations recited in claims 9-10, it would have been obvious to one of ordinary skill in the art contemplating fusing an albumin binding peptide isolated from the CDR of a single domain antibody to a cssBiTE construct as of applicant’s date of invention that a successful fusion protein will (i) bind serum albumin with at least moderate affinity, so as to prolong the serum half-life of the cssBiTE, and (ii) will be capable of mediating lysis of target cells by effector cells in the presence of human serum albumin, so as to enable therapeutic use of the cssBiTE.
As described by Revets, their albumin binding peptide derived from a single domain antibody CDR preferably has an affinity of at least better than 500 nM (see paragraph 225). Thus, the ordinarily skilled artisan preparing a C-terminal fusion of the albumin binding peptide of Revets to the cssBiTE of Kufer would have been motivated to ensure that the resulting fusion protein has an affinity for serum albumin of < 500 nM.
Moreover, since the therapeutic potential of the cssBiTE of Kufer depends on its ability to mediate lysis of target cells by effector cells in vivo, the skilled artisan would have been motivated to ensure that a cssBiTE fused to the albumin binding peptide of Revets retains an ability to mediate lysis of target cells by effector cells in vivo, i.e., even in the presence of high levels of albumin as found in human blood (see, e.g., “Human Albumin” at page 403, Section 5.5.2.1). Insofar as the reference teachings do not explicitly teach or suggest measuring the ability of the cssBiTE:albumin-binding peptide fusion protein to direct effector cells to lyse target cells in the presence of 10% human serum albumin, it nonetheless would have been obvious to the ordinarily skilled artisan to ensure that the cssBiTE:albumin-binding peptide fusion protein is capable of directing effector cells to lyse target cells even in the presence of excess human serum albumin, and such a fusion protein would necessarily also be able to mediate effector cell lysis of target cells in the presence of 10% human serum albumin.
With respect to claim 15, as described in the working examples of Kufer, the cross-species specific anti-CD3 antibodies were identified based on their ability to bind the first 27 amino acids of primate CD3 which comprise SEQ ID NO: 103, a sequence common to both human and non-human primates. Thus, the cssBiTE antibodies of Kufer will have a binding specificity as recited in claim 15.
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 13 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 Revets et al. (20080267949), 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); Stamova et al. (Molecular Immunology 49 (2011) 474– 482); Vosjan et al. (Mol Cancer Ther. 2012 Apr;11(4):1017-25 and Supplementary materials pages 1-2, Epub 2012 Feb 7, cited herewith); Humphreys (20100239582), Choi et al. (Expert Opinion on Biological Therapy, 11:7, 843-853) and “Human Albumin,” Transfus Med Hemother 2009;36:399–407, as applied to claims 1-12, 14-16, 21 and 24 above, and further for the reasons described below.
The teachings of Kufer in view of Hammond and Revets as evidenced by Baeuerle, Hopp, Stamova, Vosjan, Humphreys, Choi and Human Albumin described above teach why it would have been prima facie obvious to make a cssBiTE joined at its C-terminus to an albumin-binding peptide derived from a CDR of a single domain antibody as described by Revets.
Moreover, in paragraph 196 Hammond teaches 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. As described in paragraphs 196 of Hammond, the presence of such tags provide for convenient purification of the fusion protein.
Given the usefulness of such a tag for purification, it would have been obvious to one of ordinary skill in the art to fuse a marker sequence / peptide tag such as the HA tag to the N- or C- terminus of a cssBiTE:peptidic albumin binding moiety fusion protein. One of ordinary skill in the art would have had a reasonable expectation of successfully doing so given the teachings of Hammond demonstrating C-terminal attachment of marker sequence / peptide tag does not disrupt a BiTE from binding to its T-cell and tumor target antigens, and further given the general knowledge in the art that the N- and C- termini of antibodies are often successfully modified by fusion to marker sequence / peptide tags for the purpose of facilitating protein purification.
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.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached on M-F 9-5 EST.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644