DETAILED ACTION
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 .
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.
Priority
The present application, filed 09/26/2022, is a continuation of 15/577,929 filed 09/13/2017 (abandoned). Application 15/577,922 is acknowledged as a proper National Stage (371) entry of PCT Application No. PCT/IB2016/051750, filed 03/28/2016, which claims benefit under 35 U.S.C. 119(e) to provisional application No. 62/138,235, filed 03/25/2015.
Status of the Claims
Claims 47-53, 57, 60-67, 69-70 are pending; claims 47, 48, 57, 60-62 are amended; claims 54-56, 58-59 and 68 are canceled; claims 69 and 70 are newly recited. Claims 47-53, 57, 60-67, 69-70 are examined below.
Withdrawn Objections/Rejections
The previous objection to claim 47 is withdrawn in response to Applicant’s amendments to the claims.
The previous rejections of claims under 35 U.S.C. 112(a), regarding new matter, are withdrawn in response to Applicant’s amendments to the claims.
The previous rejection of claims under 35 U.S.C. 112(b) is withdrawn in response to Applicant’s amendments to the claims.
Claim Rejections - 35 USC § 112
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.
Written Description
Claims 47-53, 57 and 60-67 each encompass a genus of antibodies, each genus is described in terms of function, namely their binding and target antigen rather than their structure (rather than structure limiting the antibodies themselves). See specifically at claim 47 “neo-epitope antibody having high affinity for C3a, and a low affinity for C3 in a mesoscale discovery (MSD) electrochemiluminescence (ECL) immunoassay” and claim 57, the claim recites the neo-epitope “antibody has a Kd from about 10-6 to about 10-12 for C3a, and a Kd from about 10-3 to about 10-5 for C3”, thereby limiting the antibody to an antibody that targets a neoepitope, the antibody having binding for C3a, and low affinity to C3, and further described in terms by Kd (dissociation). Similarly, claim 48 “neo-epitope antibody having a high affinity for C5a, and low affinity for C5”, and claim 60 recites “the antibody has a Kd from about 10-6 to about 10-12 for C5a, and a Kd from about 10-3 to about 10-5 for C5”, thereby limiting the antibody of claim 60 to an antibody that targets a neoepitope, the antibody having the high affinity for C5a and low affinity for C5 as claimed, described in terms of Kd.
Additionally, independent claims 61 and 62 as amended also recite antibody described in terms of function and not structure, see for example claim 61, “anti-C3a antibody is a neo-epitope antibody having a high affinity for C3 and a low affinity for C3”, and claim 62, “anti-C5a antibody is a neo-epitope antibody having a high affinity for C5a and a low affinity for C5”.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. See MPEP 2163.
Claims 47 and 61 encompasses a large genus of anti-neoepitope C3a antibody, claim 60 encompasses a large genus of anti-neoepitope C5a antibody, and each genus as indicated is characterized by substantial variability. A neo-epitope antibody as claimed, is limiting the antibody to an antibody that binds to a unique epitope formed as a result of the cleavage; the antibody may for example, recognize a newly created epitope, but as claimed would fail to recognize the parent component. The present claims are not limited to any particular neo-epitope antibody or even any particular neo-epitope (any particular sequence). The present claim language and disclosure places no particular limitations on the sequences/structures of the antibodies themselves, and rather defines the antibodies only in terms of their desired binding properties (affinity, Kd).
As recited, the claims (47, 57, 48, 60-62) limit the claimed antibodies in terms of their desired binding; these limitations place no limitation on the actual structure of the claimed antibodies themselves.
“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, 418F.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). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date” (AbbVie, 759 F.3d at 1298, reiterating Enzo Biochem, Inc., 323 F.3d at 964) (emphasis added).
The specification defines a neo-epitope antibody broadly, merely indicating it is an antibody to a newly created N or C terminus of fragments on the C3a (or C5a in the case of claim 60) fragment. There are also no particular structural limitations placed on the fragment(s) to which the claimed antibodies bind. Regarding the antibodies themselves, the specification fails to disclose sufficient identifying characteristics of each claimed genus such to particularly describe the entire genera as claimed, as is discussed in more detail further below.
To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
However, for a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding, binding to a certain epitope), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
Along these same lines, a more recent Federal Circuit decision, Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), describes how when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself; not just a description of the sequence to which the antibody binds. Amgen, 872 F.3d at 1378-79.
It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date” (AbbVie, 759 F.3d at 1298, reiterating Enzo Biochem, Inc., 323 F.3d at 964)(emphasis added).
In the present case, the specification does disclose a singular species of neo-epitope antibody for each claimed genera, see specifically for C3a, commercially available C3a antibody provided by HYCULT BIOTECH (clone 2991, Catalog No. HM2074), and for C5a, antibody BNJ383 disclosed in PCT Publication WO2011/137395.
However, in the present case, there is insufficient evidence of such an established structure-function correlation in the case of antibodies that bind to the same epitopes for each of these singularly disclosed species.
A claimed invention may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art recognized correlation or relationship between the structure of the invention and its function. A biomolecule defined solely by its ability to perform a function, such as to serve as an antigen recognizing construct, without a known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. See MPEP 2163.
As discussed in the recent case of Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), see page 17:
An adequate written description must contain enough information about the actual makeup of the claimed products—“a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials,” which may be present in “functional” terminology “when the art has established a correlation between structure and function.” Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5–16) (Appellants’ expert Dr. Eck testifying that knowing “that an antibody binds to a particular amino acid on PCSK9 . . . does not tell you anything at all about the structure of the antibody”); J.A. 1314 (836:9–11) (Appellees’ expert Dr. Petsko being informed of Dr. Eck’s testimony and responding that “[m]y opinion is that [he’s] right”); Centocor, 636 F.3d at 1352 (analogizing the antibody- antigen relationship as searching for a key “on a ring with a million keys on it”) (internal citations and quotation marks omitted).
However, in the present case, even with regard to the neo-epitope(s) themselves, no structure is provided.
Regarding the antibodies themselves, the specification does not identify what particular amino acid residues of the antibodies are responsible for conferring the desired functional property of binding to neoepitopes as claimed, and also importantly (as noted previously and above) the specification lacks any structure specific to species encompassed by the present claims.
Amgen Inc. v. Sanofi further notes, pointing to Ariad Pharms., Inc. v. Eli Lilly & Co., 94 USPQ2d 1161 (Fed Cir. 2010):
To show invention, a patentee must convey in its disclosure that it “had possession of the claimed subject matter as of the filing date.” Id. at 1350. Demonstrating possession “requires a precise definition” of the invention. Id. To provide this “precise definition” for a claim to a genus, a patentee must disclose “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.” Id.
Amgen at pages 7-8.
In this case, the disclosure of a single species for each genus is insufficient to represent the entirety of each claimed genus of monoclonal antibodies having the recited functional properties. With regard to the very specific and particular functional limitations (the affinity and Kd as claimed), the only species identified in the specification are those two very specific, commercially available antibodies as indicated above.
It is not within the skill of the art to predict any and all possible substitutions that would result in products that retain the desired binding properties consistent with the individual species. Further noted, the art recognizes that structure of an antigen alone is not necessarily a reliable indicator of function.
The teachings of Harlow et al. (Antibodies, A Laboratory Manual, Cold Spring Harbor laboratory, 1988, pages 25-26 and 37-59, IDS entered 04/11/2023) which describe how the steps of the humoral immune response to an immunogen are dependent on APC, T-cell and B-cell recognition and processing of the immunogen in ways well known in the art to be highly unpredictable and heavily influenced by the particular immunogen and the specifics of the immunization protocol. Harlow et al. teach that even small changes in structure, such as loss of a single hydrogen bond, can profoundly affect antibody-antigen interaction (p. 25, last paragraph to page 26, second paragraph).
As further illustration of the unpredictability in the art, Brown et al. (“Tolerance of single, but not multiple, amino acid replacements in antibody VH CDR 2: a means of minimizing B cell wastage from somatic hypermutation?”, J Immunol. 1996 May;156(9):3285-91 (IDS entered 04/11/2023)), describes how a one amino acid change in the VHCDR2 of a particular antibody was tolerated whereas, the antibody lost binding upon introduction of two amino changes in the same region (at 3290 and Tables 1 and 2). Vajdos et al. (“Comprehensive functional maps of the antigen-binding site of an anti-ErbB2 antibody obtained with shotgun scanning mutagenesis” J Mol Biol. 2002 Jul 5;320(2):415-28, DOI: 10.1016/S0022-2836(02)00264-4 (IDS entered 04/11/2023)) teach that amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (see especially at 416). Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen.
One cannot readily or easily visualize or recognize the identities of the members of each of the claimed genera that would exhibit these claimed functional properties (binds to the neo-epitopes with the affinities as claimed, having the particular claimed Kd). The specification does not identify what particular neo-epitope(s) the antibodies bind to. Additionally, the characteristics defining the antibodies of each of the recited genus are unknown as this only sets forth what the antibodies do and not what they are. There is no disclosed partial structure or other common structural features, common to the members of the genus, which are responsible for conferring the desired function.
Recent court cases have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See AbbVie Deutschland GmbH v. Janssen Biotech. Inc. as well as Amgen v. Sanofi, as discussed above. Indeed, in Amgen the court indicates that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e. the antigen (in the present case, C3a and C5a), as knowledge of the chemical structure of an antigen does not give the required kind of structure-identifying information about the corresponding antibodies, with the antibody-antigen relationship be analogized as a search for a key on a ring with a million keys on it.
There is no structurally identifying characteristic, or core structure that is common to each of the potential various species of claimed antibody set forth, such that the ordinarily skilled artisan can readily envision which species are and are not encompassed by the claimed genera. Recitation of affinity in terms of Kd alone is merely a recitation of a desired result, rather than the actual structure/means required of the antibodies for achieving that result.
In the present case, there is no disclosure regarding the structure of the antibodies themselves, for example there is no disclosure regarding the full heavy and light chain sequences, nor disclosure of the necessary CDRs for binding. As a result, the skilled artisan cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus that exhibit the claimed binding properties.
Accordingly, for all of these reasons, the specification fails to provide adequate written description for the genus of antibody to C3a and C5a antibodies as claimed (claimed in terms of binding by their Kd value) at the recited step of “measuring”. The specification does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim Rejections - 35 USC § 103
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.
Claims 47, 49-51 and 69 are rejected under 35 U.S.C. 103 as being unpatentable over Andersson et al., C3 Adsorbed to a Polymer Surface Can Form an Initiating Alternative Pathway Convertase, The Journal of Immunology, 168, (2002), p. 5786-5791 (IDS entered 04/11/2023) in view of Meso Scale Diagnostics, Meso Scale Discovery® Clinical Immunology Applications, Product Note, https://www.mesoscale.com/~/media/files/brochures/immunologybrochure.pdf (2007), 12 pages (hereinafter referred to as The MSD technology note, IDS entered 04/11/2023), Zilow et al., Quantitation of the anaphylatoxin C3a in the presence of C3 by a novel sandwich ELISA using monoclonal antibody to a C3a neoepitope, Journal of Immunological Methods, 121, (1989), p. 261-268 (IDS entered 04/11/2013), Hycult Scope, Pentraxins, Innate immunity and inflammation, Novartis Foundation symposium, (2006), (5 pages) (IDS entered 04/11/2023) and Eberhardt et al., Human Factor H-Related Protein 2 (CFHR2) Regulates Complement Activation, PLOS One, 8(11), (2013), (11 pages) (IDS entered 04/23/2023).
Andersson et al. teach a method comprising immobilizing C3b on a sensor surface (coated on a solid phase), incubating the immobilized Cb3 in the presence of Factor B and Factor D to form C3 convertase (C3b,Bb), Andersson teach adding C3 to the incubation and incubating under conditions to cleave C3 with the C3 convertase (C3b,Bb), thereby forming C3a and C3b (see page 5787, col. 2, para 2). Andersson further teach measuring the amount of C3a by immunoassay (see page 5787, col. 2, para 3). Andersson does teach the incubation of the C3b with Factors B and D in buffer, see for example, page 5788, col. 1, the section regarding monitoring the generation of surface-bound convertase, surface coated with C3b is incubated with buffer, Factor B added, then Factor D added sequentially, thereby resulting in incubation of Cb3 in the presence of both factors. See Andersson et al. at page 5789, col. 1, last paragraph, adsorbed C3 and C3b generated convertases that cleaved C3, see Andersson teaching generation of the fluid phase C3a (see above detected by enzyme immunoassay) is evidence of the activity. Therefore, Andersson supports that measure of produced C3a is an indicator of activity (the activity of C3 convertase), consistent with the present claims.
Also, Andersson does teach C3 and C3b as substantially pure reagents (see at page 5787, end of col. 2), and does teach pure Factor B and D (page 5787, col. 1, para 2, see also teaching purified C3).
Andersson et al. fails to teach the C3b is covalently attached biotin (claim 47); and Andersson fails to teach measuring the amount of C3a using neo-epitope antibody in a mesoscale discovery electrochemiluminescence immunoassay (MSD ECL).
The MSD Technology note teaches their MSD assay materials and kits provide superior solutions as compared to traditional methods, in particular see at page 1, the MSD Technology note teaches MSD assay sensitivity can be up to 100-fold better than ELISA with a large linear range of 3-4 logs. Further at page 1, the note teaches MSD assay formats minimize both matrix effects and interference (free drug interference), thereby improving both workflow and performance. See at page 3, the MSD technology notes provides a comparison of the methods (ELISA versus MSD ECL). See also at page 4, the figure on the right, the MSD technology note also demonstrate indirect binding comprising streptavidin coated surface and biotin-tagged capture reagent (both indirect and direct binding are art recognized techniques for attaching reagent at a solid support surface).
Zilow et al. teach ELISA for quantitation of C3a, specifically Zilow disclose a two antibody sandwich assay format comprising mAb H466 with a neo-antigenic determinant, the antibody specifically binding C3a and not C3, that because the antibody preferentially binds C3a and not C3, C3 need not be removed (abstract, page 262, col. 1, para 1 and end of col. 2).
Hycult provides a commercially available anti-C3a neo-antigenic antibody for purchase (see Hycult page 3, left column, mAB chart, CAT. #HM2074 (mAB 2991)). Eberhardt et al. teach an example of immobilization of C3b to a solid phase substrate, see Eberhardt et al. teach N-biotinylated C3b bound at a sensor chip surface by way of streptavidin (streptavidin coated surface used to bind the biotinylated C3b, page 2, last paragraph at col. 1).
It would have been prima facie obvious to one having ordinary skill in the art, at the time the claimed invention was effectively filed, to have modified the assay of Andersson in order to perform an MSD ECL assay rather than the ELISA of Andersson because MSD ECL was recognized as a similar, yet superior technique, providing higher sensitivity compared to an ELISA and minimizing matrix effects, the technique known for its enhanced performance (see the MSD technology note). One of ordinary skill would have a reasonable expectation of success because of the similarity between the assay techniques, and considering the art recognized MSD ECL as a suitable alternative to ELISA.
Furthermore, it would have been obvious to have modified the assay in order to measure the amount of C3a with a C3a specific antibody, namely an anti-neoepitope C3a antibody as in Zilow et al., for example, commercially available Hycult mAB 2991, because such anti-neo-antigen antibodies were known only to bind the C3a fragments (C3a produced by complement activation), and not the parent C3 component (high affinity for C3a only by binding/detecting the neoepitope formed during compliment activation) (specifically binds the targeted analyte), thereby eliminating the need to remove C3 (Zilow), and because antibody 2991 is a commercially available antibody thereof (available for purchase). Further the modification to use an anti-neoepitope C3a antibody for the detection of C3a would have been an obvious matter of using a known reagent for its known purpose (e.g., antibody 2991 is readily available for commercial purchase), one motivated to use such an antibody because Zilow teach these reagents as highly specific. One of ordinary skill would have a reasonable expectation of success using a known reagent for its art recognized purpose (measurement by binding C3a) and because these reagents (such as 2991) were known and readily available for purchase commercially (Hycult).
Additionally, it would have been further prima facie obvious to one having ordinary skill in the art, at the time the claimed invention was effectively filed, to have immobilized C3b (to have coated the sensor/solid support surface with C3b) by way of biotin-streptavidin binding (i.e. covalent binding of biotin to the biotin binding protein streptavidin), as in Eberhardt et al., or as shown in the MSD technology note, as an obvious matter of applying a known technique to a known method. In particular the prior art contained the base method for detecting C3 convertase activity starting with sensor coated C3b, the methods comprising detection of generation of C3a, as in Andersson et al. The prior art also recognized the known technique for providing C3b on a solid support sensor, namely see Eberhardt et al. teaching immobilization of C3b at the sensor surface via biotin-streptavidin. Even further, see the MSD technology note which supports such indirect binding of capture reagent at a solid surface is well known technique in the art. One of ordinary skill in the art would have recognized that applying the binding technique for providing C3b on the sensor surface, of Eberhardt, would have yielded predictable results. Specifically the ordinarily skilled artisan would have appreciated that applying the known technique of Eberhardt to the sensor of Andersson would have resulted in covalent attachment of C3b at the sensor surface.
One of ordinary skill in the art would have had a reasonable expectation of success using a known technique for a similar method, one also having a reasonable expectation of success because Andersson is silent regarding the technique for coating the surface of the sensor with C3b and because both Eberhardt and the MSD technology note support this as a well-known technique for capture reagent attached (particularly C3b, as in Eberhardt).
Regarding claim 49, see the combination of the cited prior art teaches biotin binding protein streptavidin.
Regarding claim 50, see the combination of the cited art further teaches adding properdin with Factor B (properdin in the buffer system), page 5787, col. 2, para 2.
Regarding claim 51, see Andersson teach a ratio of 1:1 for C3b to Bb (see for example, page 5786, col 1, para 1 and page 5789, end of col. 1).
Regarding claim 69, claim 69 is similar to claim 47, however broader in scope in that claim 69 is not limited to the antibody as in claim 47 and not limited in terms of the specific assay (as such, see claim 69 is addressed presently by the combination of the cited references as applied at claim 47, and also claim 69 addressed separately in detail below).
Claim 52 is rejected under 35 U.S.C. 103 as being unpatentable over Andersson et al. and the MSD technology note, Zilow et al., Hycult and Eberhardt et al., as applied to claim 47 above, and further in view of Allnut et al., US PG Pub No. 2001/0055783A1.
Andersson et al. and the cited prior art are each as cited in detail previously above teaching a method substantially as claimed (see detailed analysis previously above), Andersson teaching the use of substantially pure (homogeneous) reagents.
Although Andersson is teaching substantially pure (homogenous) reagents, Andersson et al. fails to teach the homogeneity of each of the components of the pathway is greater than 90% (claim 52).
However, it was known by those of skill in the art at the time that the claimed invention was effectively filed, that homogeneous reagents effect quality of data in terms of consistency and sensitivity of an assay, see for example, para [0025] of Allnut et al., who teach with regard to their assay, that homogeneous reagents provide highest quality data in terms of assay consistency and sensitivity of results.
As a result, Allnut et al. further supports that homogeneity of the components of the pathway (reagents used in an assay) is an assay art recognized result effective variable, namely a variable which achieves a recognized result. Further, because the homogeneity of reagents (components) is a result effective variable, it would have been prima facie obvious to have optimized the homogeneity, in order to arrive at a homogeneity of greater than 90%, in order to achieve high quality data, assay consistency, and as a result, a highly sensitive result (as supported by Allnut). Andersson does teach substantially pure components for the assay (see as cited above); one of ordinary skill would have been motivated to have achieved the most pure, thereby arriving at homogeneity greater than 90%, out of an effort to achieve the best possible result for the assay. One of ordinary skill in the art would have had a reasonable expectation of success, considering it was known that highly homogeneous reagent was most desirable when performing an assay.
Claim 53 is rejected under 35 U.S.C. 103 as being unpatentable over Andersson et al. and the MSD technology note, Zilow et al., Hycult and Eberhardt et al., as applied to claim 47 above, and further in view of Cunnion et al., Cleavage of Complement C3b to iC3b on the Surface of Staphylococcus aureus Is Mediated by Serum Complement Factor I, Infection and Immunity, 72(5), (2004), p. 2858-2863 (IDS entered 04/11/2023).
Andersson et al. and the cited prior art are each as cited in detail previously above teaching a method substantially as claimed (see detailed analysis previously above).
However, fail to teach C3b immobilized on a solid phase that is spheres (claim 53).
Cunnion is an example in the art which uses C3b coated beads (spheres) as a solid support starting point for activity assays (see for example, Cunnion detecting Factor H activity, Factor H a component known to bind C3b and serve as a cofactor to clave C3b, see page 2858, col. 2, para 2), see page 2859, col. 1, para 3. Cunnion is further evidence that C3b retains functional ability even when immobilized at a solid support that is a sphere.
It would have been prima facie obvious to one having ordinary skill in the art, when performing the methods of Andersson et al. and the cited prior art, to have modified the solid phase microtiter substrate of Andersson in order to have used C3b coated spheres as an obvious matter of a simple substitution of one known solid phase for another, both being recognized in the art for the same purpose, namely for providing support immobilized C3b to a reaction mixture. One of ordinary skill would have a reasonable expectation of success because Cunnion demonstrates the sphere immobilized C3b retains its functional capabilities.
Claim 57 is rejected under 35 U.S.C. 103 as being unpatentable over Andersson et al. and the MSD technology note, Zilow et al., Hycult and Eberhardt et al., as applied to claim 47 above Nitsch et al., US PG Pub No. 2013/0266514A1 (IDS entered 04/11/2023).
Andersson et al. and the cited prior art teach a method substantially as claimed (see detailed analysis as above).
However, regarding claim 57, the combination of Andersson et al. and the cited art fails to teach that the anti-neo-epitope antibody of the cited art having high affinity for C5a and low affinity for C3, has a Kd from about 10-6 to about 10-12 for C3a, and Kd from about 10-3 to about to about 10-5 for C3 (HYCULT is silent with regard to antibody Kd).
Nitsch et al. is as cited in detail previously above, teaching with regard to a neoepitope specific binding specificity (a binding molecule’s ability to discriminate between the neoepitope to which it binds and a native protein), relative Kd for an antibody for a specific target epitope, for example a neoepitope, is less than binding for that antibody to other ligands (see para [0076]). Nitsch teach at para [0165], “specific binding” refers to antibody binding to a predetermined antigen, and teaches that typically the antibody binds with a dissociation constant (Kd) of 10-7 or less, and binds to the antigen with a Kd that is at least two fold less than its Kd for binding to a nonspecific antigen other than the predetermined antigen.
Therefore, although the cited art is silent as to the Kd values of their specific antibody (their neo-epitope antibody that binds preferentially to C3a compared to C3), it would have been obvious that their antibody have Kd values on the same order of magnitude as those in Nitsch, thereby addressing the presently claimed Kd values to C3a and C3 because it was known that Kd values in the ranges as claimed are common to antibodies deemed to be specific for their target (10-7 or less is a range that substantially overlaps the range of 10-6 to 10-12 as claimed). As indicated Nitsch teach such specific antibodies typically exhibit Kd two fold less than binding of the antibody for other ligands. One of ordinary skill in the art would have a reasonable expectation of success arriving at the claimed Kd values as it appears that such Kd values are common to antibodies deemed to be antigen specific (such as such neo-epitope antibodies which distinguish their antigen from their native counterpart), and the claimed antibody is disclosed by the prior art (Zilow) as being highly specific, therefore it would be expected to have a very low Kd value.
Claim(s) 48, 63, 65 and 70 are rejected under 35 U.S.C. 103 as being unpatentable over Krych-Goldberg et al., Decay Accelerating Activity of Complement Receptor Type I (CD35), The Journal of Biological Chemistry, 274(44), (1999), p. 31160-31168 (IDS entered 04/11/2023) in view of Oppermann et al., A sensitive Enzyme Immunoassay for the Quantitation of Human C5a/C5a (desArg) Anaphylatoxin Using a Monoclonal Antibody with Specificity for a Neoepitope, Complement Inflamm, 8, (1991), p. 13-24 (IDS entered 04/11/2023), Eberhardt et al., Human Factor H-Related Protein 2 (CFHR2) Regulates Complement Activation, PLOS One, 8(11), (2013), (11 pages) (IDS entered 04/11/2023) and Meso Scale Diagnostics, MSD Technology Platform, Product Note, https://www.mesoscale.com/~/media/files/brochures/techbrochure.pdf?la=en, (2011), 12 pages (hereinafter referred to as The MSD technology note 2011).
Krych-Goldberg et al. teach a microtiter plate assay for the alternative pathway decay accelerating activity (see regulators of complement activation proteins accelerate the dissociation of C3 and C5 convertases, page 31160, col. 2, para 2). See Krych-Goldberg et al., the microtiter plate assay comprising C3b coated microtiter plates incubated in the presence of Factors B and D in a buffer (see veronal buffer) to form C3 convertase, adding C3 to the incubation and incubating under conditions sufficient to cleave C3 with the C3 convertase to form C3a and C3b, further measuring C3a with an immunoassay (RIA) (see page 31162, col. 2, last paragraph).
Krych-Goldberg also teach purified C3 (page 31161, col. 2, para 2), as well as purified Factors B and D (see page 31163, col. 2, para 1) and purified C3b, thereby addressing wherein each of the individual components are substantially homogeneous.
See Krych-Goldberg et al. also teach at the citation for the microtiter plate assay for the alternative pathway DAA, the assay was also performed as a C5 convertase assay, the differences in methodology being that the wells of the plate were coated with C3b dimer, the assay using different amounts of Factors B and D. See also as cited previously, Krych-Goldberg teach their assays comprising substantially homogeneous individual components (see relies on purified reagents).
Krych-Goldberg et al. fails to teach the C3b dimer is covalently attached to a tag comprising biotin or an analog or derivative thereof (claim 48). Krych-Goldberg et al. is also silent as to whether or not the C5 convertase assay, similar to the C3 convertase assay, detects generation of the cleavage product that results. Put another way, Krych-Goldberg is silent as to whether immunoassay is performed in order to detect C5a. Finally, Krych-Goldberg fails to teach immunoassay is an ELISA or MSD.
Eberhardt et al. teach an example of immobilization of C3b to a solid phase substrate, see Eberhardt et al. teach N-biotinylated C3b bound at a sensor chip surface by way of streptavidin (streptavidin coated surface used to bind the biotinylated C3b, page 2, last paragraph at col. 1).
Oppermann et al. teach that C5a is generated during activation of the alternative pathway of complement, that cleavage by specific C5 convertases results in liberation of C5a (page 13, col. 1, para 1). Oppermann et al. teach their assay as a high sensitive ELISA for detection of C5a, that the assay is based on the monoclonal antibody with specificity for a neo-epitope on C5a/C5a (desArg) (that the antibody is highly specific for C5a, not C5, i.e. can achieve specific detection in the presence of C5, see page 14, col. 1, para 1, page 21, col. 1, para 2, page 22, col. 1, para 1).
The MSD technology note (2011) teaches MSD ECL assay format as an alternative to traditional assay such as ELISA and RIA because MSD assays improve sensitivity, expand dynamic range, and work well in difficult sample types (see paragraph 1 of page 4 of the MSD technology note 2011).
It would have been prima facie obvious to one having ordinary skill in the art, at the time the claimed invention was effectively filed, to have coated the C3b to the solid support (the microtiter plate) by way of biotin-streptavidin binding (i.e. covalent binding of biotin to the biotin binding protein streptavidin), as in Eberhardt et al. as an obvious matter of applying a known technique to a known method. In particular the prior art contained the base method for detecting C3 convertase activity (detecting cleavage) starting with sensor coated C3b, the methods comprising detection of generation of C3a, as in Krych-Goldberg et al. The prior art also recognized the known technique for providing C3b on a solid support sensor, namely see Eberhardt et al. teaching immobilization of C3b at the sensor surface via biotin-streptavidin. One of ordinary skill in the art would have recognized that applying the binding technique for providing C3b on the sensor surface, of Eberhardt, would have yielded predictable results. Specifically, the ordinarily skilled artisan would have appreciated that applying the known technique of Eberhardt to the sensor of Krych-Goldberg would have resulted in covalent attachment of C3b at the sensor surface. One of ordinary skill in the art would have had a reasonable expectation of success using a known technique for a similar method.
Similarly as above, because both techniques for providing C3b coated surface were known in the art (see it was known that one could coat a surfaces as in Krych-Goldberg or coat a surface using biotin-streptavidin binding at the surface), it also would have been an obvious matter of a simple substitution of one know technique for providing C3b at a solid support surface for another. Further, because both were known ways of providing C3b at the solid support surface, one would have a reasonable expectation of success substituting one for the other.
In addition, it would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have detected the C5 convertase activity by way of immunoassay (antibody binding assay), namely by targeting C5a, detecting C5a by way of neo-epitope binding antibody as in Oppermann et al. (antibody with high affinity for C5a, and not C5). It would have been obvious to detect C5a in this manner as an obvious matter of applying a known assay technique (antibody binding immunoassay for C5a) for its known purpose (to detect C5a convertase activity, which Krych-Goldberg is teaching assay for C5a convertase in addition to the C3a convertase), particularly because it was known that C5a indicates C5 convertase activity (Oppermann and also Krych-Goldberg), one also being motivated to rely on antibody reagent (antibody that targets C5a over C5) as in Oppermann because such assay technique is considered a highly sensitive assay which specifically binds and detects C5a over C5 (high affinity for C5a with low affinity for C5, taught as more specific than those techniques in the prior art at the time of Oppermann). One of ordinary skill would have a reasonable expectation of success because Oppermann teach detection that is specific and sensitive detection of C5a.
It would have been prima facie obvious to one having ordinary skill in the art, at the time the claimed invention was effectively filed, to have modified the assay of Krych-Goldberg et al. in order to perform an MSD ECL assay rather than the RIA because MSD ECL was recognized as a superior immunoassay technique, providing higher sensitivity compared to traditional methods such as ELISA and RIA, expanded dynamic range and applicable even with difficult samples (see the MSD technology note 2011). One of ordinary skill would have a reasonable expectation of success because MSD ECL is an art recognized superior alternative to RIA. Krych-Goldberg et al., with Eberhardt et al. and Oppermann et al. addresses immunoassay comprising detecting C5a with an antibody having high affinity for C5a and low affinity for C5 (see Oppermann’s antibody binds and detects C5a in presence of C5).
Regarding claim 63, see the above combination of the cited art addresses biotin binding protein comprising streptavidin.
Regarding claim 65, see Krych-Goldberg et al. teach a ratio of C3b to Bb of 1:1 (C3bBb, see page 31163, end of col. 1).
Regarding claim 70, claim 70 is similar to claim 48, however broader in scope in that claim 70 is not limited to the antibody as in claim 48 and not limited in terms of the specific assay (as such, see claim 70 is addressed presently by the combination of the cited references as applied at claim 48, and also claim 70 addressed separately in detail below).
Claim 60 is rejected under 35 U.S.C. 103 as being unpatentable over Krych-Goldberg et al. in view of Oppermann et al., Eberhardt et al. and Meso Scale Diagnostics, as applied to claim 48 above, and further in view Nitsch et al. (IDS entered 04/11/2023).
Krych-Goldberg et al. and the cited prior art teach a method substantially as claimed (see detailed analysis as above).
However, regarding claim 60, the combination of Krych-Goldberg et al. and the cited art fails to teach that the antibody of Oppermann having high affinity for C5a and low affinity for C5, has a Kd from about 10-6 to about 10-12 for C5a, and Kd from about 10-3 to about to about 10-5 for C5 (Zilow is silent with regard to antibody Kd).
Nitsch et al. is as cited in detail previously above, teaching with regard to a neoepitope specific binding specificity (a binding molecule’s ability to discriminate between the neoepitope to which it binds and a native protein), relative Kd for an antibody for a specific target epitope, for example a neoepitope, is less than binding for that antibody to other ligands (see para [0076]). Nitsch teach at para [0165], “specific binding” refers to antibody binding to a predetermined antigen, and teaches that typically the antibody binds with a dissociation constant (Kd) of 10-7 or less, and binds to the antigen with a Kd that is at least two fold less than its Kd for binding to a nonspecific antigen other than the predetermined antigen.
Therefore, although Oppermann is silent as to the Kd values of their specific antibody (their neo-epitope antibody that binds preferentially to C5a compared to C5), it would have been obvious that their antibody have Kd values on the same order of magnitude as those in Nitsch, thereby addressing the presently claimed Kd values to C5a and C5 because it was known that Kd values in the ranges as claimed are common to antibodies deemed to be specific for their target (10-7 or less is a range that substantially overlaps the range of 10-6 to 10-12 as claimed). As indicated Nitsch teach such specific antibodies typically exhibit Kd two fold less than binding of the antibody for other ligands. One of ordinary skill in the art would have a reasonable expectation of success arriving at the claimed Kd values as it appears that such Kd values are common to antibodies deemed to be antigen specific (such as such neo-epitope antibodies which distinguish their antigen from their native counterpart), and the claimed antibody is disclosed by the prior art (Zilow) as being highly specific, therefore it would be expected to have a very low Kd value.
Claim 64 is rejected under 35 U.S.C. 103 as being unpatentable over Krych-Goldberg et al. in view of Oppermann et al., Eberhardt et al. and Meso Scale Diagnostics, as applied to claim 48 above, and further in view of Andersson et al. and Hourcade et al., The Role of Properdin in the Assembly of the Alternative Pathway C3 Convertase of Complement, The Journal of Biological Chemistry, 281(4), (2006), p. 2128-2132 (IDS entered 04/11/2023).
Krych-Goldberg et al. and the cited prior art teaches a method substantially as claimed. However, fails to teach the buffer further comprises properdin and/or a serum free and gelatin free buffer (claim 64).
Andersson et al. similarly teach an assay for generating convertase cleavage products (for example C3a), Andersson is similar to that of Krych-Goldberg in Andersson’s method similarly starts with immobilized C3b, the method teaching addition of Factors B and D in order to create convertase (C3b,Bb), see page 5787, col. 2, paras 2 and 3). See Andersson et al. is an example in the art teaching addition of properdin to the buffer with Factor B (citation at page 5787, col. 2, para 2).
Although Andersson et al. fails to teach addition of properdin to improve detection of C5a following addition, see Hourcade, who teaches properdin is known to have a stabilizing effect (abstract). See for example, Figure 6, regarding the role of properdin and its binding involved with the formation of convertases.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the buffer mixture to have further included properdin, as in Andersson’s reaction mixture, because properdin is known in the art to have a stabilizing effect during the formation of convertases (Andersson and Hourcade) . One of ordinary skill would have a reasonable expectation of success because Andersson teach the alternative pathway convertases are able to form in the presence of properdin.
Claim 66 is rejected under 35 U.S.C. 103 as being unpatentable over Krych-Goldberg et al. in view of Oppermann et al., Eberhardt et al. and Meso Scale Diagnostics, as applied to claim 48 above, and further in view of Allnut et al.
Krych-Goldberg et al. and the cited prior art are each as cited in detail previously above teaching a method substantially as claimed (see detailed analysis previously above), see Krych-Goldberg et al. as cited above, teaching substantially homogeneous individual components.
Krych-Goldberg et al. fails to teach the homogeneity of each of the components of the pathway is greater than about 90% (claim 66).
However, it was known by those of skill in the art at the time that the claimed invention was effectively filed, that homogeneous reagents effect quality of data in terms of consistency and sensitivity of an assay, see for example, para [0025] of Allnut et al., who teach with regard to their assay, that homogeneous reagents provide highest quality data in terms of assay consistency and sensitivity of results.
As a result, Allnut et al. further supports that homogeneity of the components of the pathway (reagents used in an assay) is an assay art recognized result effective variable, namely a variable which achieves a recognized result. Further, because the homogeneity of reagents (components) is a result effective variable, it would have been prima facie obvious to have optimized the homogeneity, in order to arrive at a homogeneity of greater than 90%, in order to achieve high quality data, assay consistency, and as a result, a highly sensitive result (as supported by Allnut). Krych-Goldberg et al. does teach substantially pure components for the assay (see as cited above); one of ordinary skill would have been motivated to have achieved the most pure, thereby arriving at homogeneity greater than 90%, out of an effort to achieve the best possible result for the assay. One of ordinary skill in the art would have had a reasonable expectation of success, considering it was known that highly homogeneous reagent was most desirable when performing an assay.
Claim 67 is rejected under 35 U.S.C. 103 as being unpatentable over Krych-Goldberg et al. in view of Oppermann et al., Eberhardt et al. and Meso Scale Diagnostics, as applied to claim 48 above, and further in view of Cunnion et al., Cleavage of Complement C3b to iC3b on the Surface of Staphylococcus aureus Is Mediated by Serum Complement Factor I, Infection and Immunity, 72(5), (2004), p. 2858-2863.
Krych-Goldberg et al. and the cited prior art are each as cited in detail previously above teaching a method substantially as claimed (see detailed analysis previously above).
However, Krych-Goldberg et al. fail to teach C3b immobilized on a solid phase that is spheres (claim 67).
Cunnion is an example in the art which uses C3b coated beads (spheres) as a solid support starting point for activity assays (see for example, Cunnion detecting Factor H activity, Factor H a component known to bind C3b and serve as a cofactor to clave C3b, see page 2858, col. 2, para 2), see page 2859, col. 1, para 3. Cunnion is further evidence that C3b retains functional ability even when immobilized at a solid support that is a sphere.
It would have been prima facie obvious to one having ordinary skill in the art, when performing the methods of Krych-Goldberg et al. and the cited prior art, to have modified the solid phase microtiter substrate of Krych-Goldberg in order to have used C3b coated spheres as an obvious matter of a simple substitution of one known solid phase for another, both being recognized in the art for the same purpose, namely for providing support immobilized C3b to a reaction mixture. One of ordinary skill would have a reasonable expectation of success because Cunnion demonstrates the sphere immobilized C3b retains its functional capabilities.
Claim(s) 61 is rejected under 35 U.S.C. 103 as being unpatentable over Andersson et al., C3 Adsorbed to a Polymer Surface Can Form an Initiating Alternative Pathway Convertase, The Journal of Immunology, 168, (2002), p. 5786-5791 in view of Eberhardt et al., Human Factor H-Related Protein 2 (CFHR2) Regulates Complement Activation, PLOS One, 8(11), (2013), (11 pages), Zilow et al., Quantitation of the anaphylatoxin C3a in the presence of C3 by a novel sandwich ELISA using monoclonal antibody to a C3a neoepitope, Journal of Immunological Methods, 121, (1989), p. 261-268 and Zuk et al., US 4,208,479.
Andersson et al. teach a method comprising immobilizing C3b on a sensor surface (coated on a solid phase), incubating the immobilized Cb3 in the presence of Factor B and Factor D to form C3 convertase (C3b,Bb), Andersson teach adding C3 to the incubation and incubating under conditions to cleave C3 with the C3 convertase (C3b,Bb), thereby forming C3a and C3b (see page 5787, col. 2, para 2). Andersson further teach measuring the amount of C3a by immunoassay (see page 5787, col. 2, para 3). Andersson does teach the incubation of the C3b with Factors B and D in buffer, see for example, page 5788, col. 1, the section regarding monitoring the generation of surface-bound convertase, surface coated with C3b is incubated with buffer, Factor B added, then Factor D added sequentially, thereby resulting in incubation of Cb3 in the presence of both factors. See Andersson et al. at page 5789, col. 1, last paragraph, adsorbed C3 and C3b generated convertases that cleaved C3, see Andersson teaching generation of the fluid phase C3a (see above detected by enzyme immunoassay using anti-C3a antibody) is evidence of the activity. Therefore, Andersson supports that measure of produced C3a is an indicator of activity (the activity of C3 convertase), consistent with the present claims.
Also, Andersson does teach C3 and C3b as substantially pure reagents (see at page 5787, end of col. 2), and does teach pure Factor B and D (page 5787, col. 1, para 2, see also teaching purified C3).
Andersson et al. fails to teach the C3b is covalently attached biotin or an analog or derivative thereof (i.e., fails to teach attachment by biotinylated C3b and streptavidin coated substrate). Further, as a result, the reference fails to recite providing the components required for the assay for C3 convertase activity together as a kit (product). Also fails to teach the anti-C3a antibody is a neo-epitope antibody having high affinity for C3a and low affinity for C3.
Eberhardt et al. teach an example of immobilization of C3b to a solid phase substrate, see Eberhardt et al. teach N-biotinylated C3b bound at a sensor chip surface by way of streptavidin (streptavidin coated surface used to bind the biotinylated C3b, page 2, last paragraph at col. 1).
Zilow et al. teach ELISA for quantitation of C3a, specifically Zilow disclose a two antibody sandwich assay format comprising mAb H466 with a neo-antigenic determinant, the antibody specifically binding C3a and not C3, that because the antibody preferentially binds C3a and not C3, C3 need not be removed (abstract, page 262, col. 1, para 1 and end of col. 2).
Zuk et al. teach that in performing assays, it is convenient and to combine the necessary reagents together in a kit (column 22, lines 20-68 in particular). Zuk et al. further teach that this may improve assay accuracy.
It would have been further prima facie obvious to one having ordinary skill in the art, at the time the claimed invention was effectively filed, to have immobilized C3b (to have coated the sensor/solid support surface with C3b) by way of biotin-streptavidin binding (i.e. covalent binding of biotin to the biotin binding protein streptavidin), as in Eberhardt et al., as an obvious matter of applying a known technique to a known method. In particular the prior art contained the base method for detecting C3 convertase activity starting with sensor coated C3b, the methods comprising detection of generation of C3a, as in Andersson et al. The prior art also recognized the known technique for providing C3b on a solid support sensor, namely see Eberhardt et al. teaching immobilization of C3b at the sensor surface via biotin-streptavidin. One having ordinary skill in the art would have recognized that by applying the binding technique for providing C3b on the sensor surface, of Eberhardt, one would have yielded predictable results. Specifically, the ordinarily skilled artisan would have appreciated that applying the known technique of Eberhardt to the sensor of Andersson would have resulted in covalent attachment of C3b at the sensor surface. One of ordinary skill in the art would have had a reasonable expectation of success using a known technique for a similar method, one also having a reasonable expectation of success because Andersson is silent regarding the technique for coating the surface of the sensor with C3b and because Eberhardt this as a known technique for capture reagent attachment (particularly C3b, as in Eberhardt).
Furthermore, it would have been obvious to have modified the assay antibody in order to provide as the antibody an anti-neoepitope C3a antibody as in Zilow et al., because such anti-neo-antigen antibodies were known only to bind the C3a fragments (C3a produced by complement activation), and not the parent C3 component (high affinity for C3a only by binding/detecting the neoepitope formed during compliment activation) (specifically binds the targeted analyte), thereby eliminating the need to remove C3 (Zilow). Further the modification to provide an anti-neoepitope C3a antibody intended for the detection of C3a would have been an obvious matter of providing a known reagent for its known purpose, one motivated to provide such an antibody because Zilow teach these reagents as highly specific. One of ordinary skill would have a reasonable expectation of success providing a known reagent for its art recognized purpose (measurement by binding C3a).
As cited above, considering Zuk, it would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have provided the assay components for measuring activity of C3 convertase as taught by Andersson et al. in view of the cited art, together in kit form for convenience and accuracy as taught by Zuk et al. One having a reasonable expectation of success given that all of the components of the assay are required for measuring activity.
Claim(s) 62 is rejected under 35 U.S.C. 103 as being unpatentable over Krych-Goldberg et al., Decay Accelerating Activity of Complement Receptor Type I (CD35), The Journal of Biological Chemistry, 274(44), (1999), p. 31160-31168 in view of Oppermann et al., A sensitive Enzyme Immunoassay for the Quantitation of Human C5a/C5a (desArg) Anaphylatoxin Using a Monoclonal Antibody with Specificity for a Neoepitope, Complement Inflamm, 8, (1991), p. 13-24, Eberhardt et al., Human Factor H-Related Protein 2 (CFHR2) Regulates Complement Activation, PLOS One, 8(11), (2013), (11 pages) and Zuk et al., US 4,208,479.
Krych-Goldberg et al. teach an assay and reagents for measuring C5 convertase activity (see as cited in detail previously above).
Regarding the assay components, Krych-Goldberg et al. fails to teach the C3b dimer is covalently attached to a tag comprising biotin or an analog or derivative thereof, and fails to specifically teach reagent such as anti-C5 antibody. Further, as a result, the reference fails to recite providing the components required for the assay for C5 convertase activity together as a kit (product).
Eberhardt et al. is as cited above, and teach an example of immobilization of C3b to a solid phase substrate, see Eberhardt et al. teach N-biotinylated C3b bound at a sensor chip surface by way of streptavidin (streptavidin coated surface used to bind the biotinylated C3b, page 2, last paragraph at col. 1).
Oppermann et al. is as cited above, and teach that C5a is generated during activation of the alternative pathway of complement, that cleavage by specific C5 convertases results in liberation of C5a (page 13, col. 1, para 1). Oppermann et al. teach their assay as a high sensitive ELISA for detection of C5a, that the assay is based on the monoclonal antibody with specificity for a neo-epitope on C5a/C5a (desArg) (that the antibody is highly specific for C5a, not C5, i.e. can achieve specific detection in the presence of C5, see page 14, col. 1, para 1, page 21, col. 1, para 2, page 22, col. 1, para 1).
However, Zuk et al. teach that in performing assays, it is convenient and to combine the necessary reagents together in a kit (column 22, lines 20-68 in particular). Zuk et al. further teach that this may improve assay accuracy.
It would have been prima facie obvious to have modified the assay of Krych-Goldberg et al. with the teachings of Eberhardt et al. and Oppermann et al. for the reasons as discussed in detail previously above. Krych-Goldberg et al. in view of the cited art is teaching the components for measuring protease activity of C5 convertase of the alternative pathway, substantially as claimed (see as cited above, substantially homogeneous C3b covalently attached via biotin, solid phase comprising biotin binding protein, and substantially homogenous reagents, as well as anti-C5a antibody).
See Zuk et al., as cited above, considering Zuk, it would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to have provided the assay components for measuring activity of C5 convertase as taught by Krych-Goldberg et al. in view of the cited art, together in kit form for convenience and accuracy as taught by Zuk et al. One having a reasonable expectation of success given that all of the components of the assay are required for measuring activity.
Claim 69 are rejected under 35 U.S.C. 103 as being unpatentable over Andersson et al., C3 Adsorbed to a Polymer Surface Can Form an Initiating Alternative Pathway Convertase, The Journal of Immunology, 168, (2002), p. 5786-5791 in view of Meso Scale Diagnostics, Meso Scale Discovery® Clinical Immunology Applications, Product Note, https://www.mesoscale.com/~/media/files/brochures/immunologybrochure.pdf (2007), 12 pages (hereinafter referred to as The MSD technology note), and Eberhardt et al., Human Factor H-Related Protein 2 (CFHR2) Regulates Complement Activation, PLOS One, 8(11), (2013), (11 pages).
Andersson et al. teach a method comprising immobilizing C3b on a sensor surface (coated on a solid phase), incubating the immobilized Cb3 in the presence of Factor B and Factor D to form C3 convertase (C3b,Bb), Andersson teach adding C3 to the incubation and incubating under conditions to cleave C3 with the C3 convertase (C3b,Bb), thereby forming C3a and C3b (see page 5787, col. 2, para 2). Andersson further teach measuring the amount of C3a by immunoassay (see page 5787, col. 2, para 3, i.e., detecting via antibody).
Andersson does teach the incubation of the C3b with Factors B and D in buffer, see for example, page 5788, col. 1, the section regarding monitoring the generation of surface-bound convertase, surface coated with C3b is incubated with buffer, Factor B added, then Factor D added sequentially, thereby resulting in incubation of Cb3 in the presence of both factors. See Andersson et al. at page 5789, col. 1, last paragraph, adsorbed C3 and C3b generated convertases that cleaved C3, see Andersson teaching generation of the fluid phase C3a (see above detected by enzyme immunoassay) is evidence of the activity. Therefore, Andersson supports that measure of produced C3a is an indicator of activity (the activity of C3 convertase), consistent with the present claims.
Also, Andersson does teach C3 and C3b as substantially pure reagents (see at page 5787, end of col. 2), and does teach pure Factor B and D (page 5787, col. 1, para 2, see also teaching purified C3).
Andersson et al. fails to teach the C3b is covalently attached biotin (claim 69).
The MSD Technology note teaches their MSD assay materials and kits provide superior solutions as compared to traditional methods, in particular see at page 1, the MSD Technology note teaches MSD assay sensitivity can be up to 100-fold better than ELISA with a large linear range of 3-4 logs. Further at page 1, the note teaches MSD assay formats minimize both matrix effects and interference (free drug interference), thereby improving both workflow and performance. See at page 3, the MSD technology notes provides a comparison of the methods (ELISA versus MSD ECL). See also at page 4, the figure on the right, the MSD technology note also demonstrate indirect binding comprising streptavidin coated surface and biotin-tagged capture reagent (both indirect and direct binding are art recognized techniques for attaching reagent at a solid support surface).
Eberhardt et al. teach an example of immobilization of C3b to a solid phase substrate, see Eberhardt et al. teach N-biotinylated C3b bound at a sensor chip surface by way of streptavidin (streptavidin coated surface used to bind the biotinylated C3b, page 2, last paragraph at col. 1).
It would have been prima facie obvious to one having ordinary skill in the art, at the time the claimed invention was effectively filed, to have modified the assay of Andersson in order to perform an MSD ECL assay rather than the ELISA of Andersson because MSD ECL was recognized as a similar, yet superior technique, providing higher sensitivity compared to an ELISA and minimizing matrix effects, the technique known for its enhanced performance (see the MSD technology note). One of ordinary skill would have a reasonable expectation of success because of the similarity between the assay techniques, and considering the art recognized MSD ECL as a suitable alternative to ELISA.
Additionally, it would have been further prima facie obvious to one having ordinary skill in the art, at the time the claimed invention was effectively filed, to have immobilized C3b (to have coated the sensor/solid support surface with C3b) by way of biotin-streptavidin binding (i.e. covalent binding of biotin to the biotin binding protein streptavidin), as in Eberhardt et al., or as shown in the MSD technology note, as an obvious matter of applying a known technique to a known method. In particular the prior art contained the base method for detecting C3 convertase activity starting with sensor coated C3b, the methods comprising detection of generation of C3a, as in Andersson et al. The prior art also recognized the known technique for providing C3b on a solid support sensor, namely see Eberhardt et al. teaching immobilization of C3b at the sensor surface via biotin-streptavidin. Even further, see the MSD technology note which supports such indirect binding of capture reagent at a solid surface is well known technique in the art. One of ordinary skill in the art would have recognized that applying the binding technique for providing C3b on the sensor surface, of Eberhardt, would have yielded predictable results.
Specifically, the ordinarily skilled artisan would have appreciated that applying the known technique of Eberhardt to the sensor of Andersson would have resulted in covalent attachment of C3b at the sensor surface. One of ordinary skill in the art would have had a reasonable expectation of success using a known technique for a similar method, one also having a reasonable expectation of success because Andersson is silent regarding the technique for coating the surface of the sensor with C3b and because both Eberhardt and the MSD technology note support this as a well-known technique for capture reagent attached (particularly C3b, as in Eberhardt).
Claim 70 is rejected under 35 U.S.C. 103 as being unpatentable over Krych-Goldberg et al., Decay Accelerating Activity of Complement Receptor Type I (CD35), The Journal of Biological Chemistry, 274(44), (1999), p. 31160-31168 (IDS entered 04/11/2023) in view of Oppermann et al., A sensitive Enzyme Immunoassay for the Quantitation of Human C5a/C5a (desArg) Anaphylatoxin Using a Monoclonal Antibody with Specificity for a Neoepitope, Complement Inflamm, 8, (1991), p. 13-24 (IDS entered 04/11/2023) and Eberhardt et al., Human Factor H-Related Protein 2 (CFHR2) Regulates Complement Activation, PLOS One, 8(11), (2013), (11 pages) (IDS entered 04/11/2023) and.
Krych-Goldberg et al. teach a microtiter plate assay for the alternative pathway decay accelerating activity (see regulators of complement activation proteins accelerate the dissociation of C3 and C5 convertases, page 31160, col. 2, para 2). See Krych-Goldberg et al., the microtiter plate assay comprising C3b coated microtiter plates incubated in the presence of Factors B and D in a buffer (see veronal buffer) to form C3 convertase, adding C3 to the incubation and incubating under conditions sufficient to cleave C3 with the C3 convertase to form C3a and C3b, further measuring C3a with an immunoassay (RIA) (see page 31162, col. 2, last paragraph).
Krych-Goldberg also teach purified C3 (page 31161, col. 2, para 2), as well as purified Factors B and D (see page 31163, col. 2, para 1) and purified C3b, thereby addressing wherein each of the individual components are substantially homogeneous.
See Krych-Goldberg et al. also teach at the citation for the microtiter plate assay for the alternative pathway DAA, the assay was also performed as a C5 convertase assay, the differences in methodology being that the wells of the plate were coated with C3b dimer, the assay using different amounts of Factors B and D. See also as cited previously, Krych-Goldberg teach their assays comprising substantially homogeneous individual components (see relies on purified reagents).
Krych-Goldberg et al. fails to teach the C3b dimer is covalently attached to a tag comprising biotin or an analog or derivative thereof (claim 70). Krych-Goldberg et al. is also silent as to whether or not the C5 convertase assay, similar to the C3 convertase assay, detects generation of the cleavage product that results. Put another way, Krych-Goldberg is silent as to whether immunoassay is performed in order to detect C5a.
Eberhardt et al. teach an example of immobilization of C3b to a solid phase substrate, see Eberhardt et al. teach N-biotinylated C3b bound at a sensor chip surface by way of streptavidin (streptavidin coated surface used to bind the biotinylated C3b, page 2, last paragraph at col. 1).
Oppermann et al. teach that C5a is generated during activation of the alternative pathway of complement, that cleavage by specific C5 convertases results in liberation of C5a (page 13, col. 1, para 1). Oppermann et al. teach their assay as a high sensitive ELISA for detection of C5a, that the assay is based on the monoclonal antibody with specificity for a neo-epitope on C5a/C5a (desArg) (that the antibody is highly specific for C5a, not C5, i.e. can achieve specific detection in the presence of C5, see page 14, col. 1, para 1, page 21, col. 1, para 2, page 22, col. 1, para 1).
It would have been prima facie obvious to one having ordinary skill in the art, at the time the claimed invention was effectively filed, to have coated the C3b to the solid support (the microtiter plate) by way of biotin-streptavidin binding (i.e. covalent binding of biotin to the biotin binding protein streptavidin), as in Eberhardt et al. as an obvious matter of applying a known technique to a known method. In particular the prior art contained the base method for detecting C3 convertase activity (detecting cleavage) starting with sensor coated C3b, the methods comprising detection of generation of C3a, as in Krych-Goldberg et al. The prior art also recognized the known technique for providing C3b on a solid support sensor, namely see Eberhardt et al. teaching immobilization of C3b at the sensor surface via biotin-streptavidin. One of ordinary skill in the art would have recognized that applying the binding technique for providing C3b on the sensor surface, of Eberhardt, would have yielded predictable results. Specifically, the ordinarily skilled artisan would have appreciated that applying the known technique of Eberhardt to the sensor of Krych-Goldberg would have resulted in covalent attachment of C3b at the sensor surface. One of ordinary skill in the art would have had a reasonable expectation of success using a known technique for a similar method.
Similarly, as above, because both techniques for providing C3b coated surface were known in the art (see it was known that one could coat a surface as in Krych-Goldberg or coat a surface using biotin-streptavidin binding at the surface), it also would have been an obvious matter of a simple substitution of one know technique for providing C3b at a solid support surface for another. Further, because both were known ways of providing C3b at the solid support surface, one would have a reasonable expectation of success substituting one for the other.
In addition, it would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have detected the C5 convertase activity by way of immunoassay (antibody binding assay), namely by targeting C5a, detecting C5a by way of neo-epitope binding antibody as in Oppermann et al. (antibody with high affinity for C5a, and not C5). It would have been obvious to detect C5a in this manner as an obvious matter of applying a known assay technique (antibody binding immunoassay for C5a) for its known purpose (to detect C5a convertase activity, which Krych-Goldberg is teaching assay for C5a convertase in addition to the C3a convertase), particularly because it was known that C5a indicates C5 convertase activity (Oppermann and also Krych-Goldberg), one also being motivated to rely on antibody reagent (antibody that targets C5a over C5) as in Oppermann because such assay technique is considered a highly sensitive assay which specifically binds and detects C5a over C5 (high affinity for C5a with low affinity for C5, taught as more specific than those techniques in the prior art at the time of Oppermann). One of ordinary skill would have a reasonable expectation of success because Oppermann teach detection that is specific and sensitive detection of C5a.
Response to Arguments
Applicant's arguments filed 02/26/2026 have been fully considered but they are not persuasive for the following reasons:
Regarding remarks at page 7, see as indicated above the previous objection to claim 47 and the rejection of claims under 35 U.S.C. 112(a) regarding new matter, are withdrawn in response to Applicant’s amendments to the claims.
Regarding the rejection of claims under 35 U.S.C. 112(a), for insufficient written description, at remarks pages 7-12 Applicant argues the rejection. Applicant refers to a presentation given by the Office, entitled “antibodies and the written description requirement under 35 U.S.C. 112(a) (referred to as Appendix A), in which it was acknowledged that claims directed to methods of using a genus of antibodies meet the requirement if the “totality of evidence indicates a genus of antibodies within the scope of the claim exists” and there “is scientific reason to believe that any of the antibodies in the art will work in the claimed method”. Applicant argues that during the presentation, it was acknowledged that exemplification of a single antibody in a claimed method provides sufficient written description for a genus of antibodies, given that the genus of antibodies “was known and readily available in the art” at the relevant filing.
Applicant further argues analogous Example 7 in the presentation, the present claims are directed to methods, which involve the use of a genus of antibodies were well known and readily available in the art. Applicant argues the claims are drawn to a method of measuring protease activity of C3 or C5 convertase that employs neo-epitope antibodies which have a higher affinity for C3a or C5a than for C3 or C5, respectively, not the neo-epitope antibodies themselves, and thus the relevant inquiry is whether possession is shown for a method of measurement that employs neo-epitope antibodies rather than for the particular neo-epitope antibodies used int eh methods.
However, in response to Applicant’s arguments, the instant claims differ from Example 7 in the referenced presentation in that they do not merely recite a neo-epitope antibody that binds the target C3a or C5a, rather the claims place additional functional limitations on the claim, for example that it binds C3a with higher affinity than C3 (and C5a with higher affinity than C5), and further limits the antibodies to only those neo-epitope antibodies exhibiting the specifically claimed Kd .
Additionally, in response to remarks, although the invention is not directed to the antibodies, themselves, the recited genus of antibodies are a critical feature/element of the claimed method and as such is required to satisfy the requirement for written description. The claimed method is not open to just any antibody that is a neo-epitope antibody, but rather only those that achieved the desired binding as claimed (referring to the specific affinity requirements as recited). As a result, unlike example 7, the present claims do not meet the requirement under 35 U.S.C. 112(a).
Referring to Applicant’s submitted evidence Appendix A at slide number 20, and consistent with MPEP 2163 (II)(A)(3)(a)(ii), the written description requirement for a claimed genus may be satisfied through description of a representative number of species, disclosure or relevant identifying characteristics, and/or by functional characteristics coupled with a known disclosed correlation between function and structure.
If it is Applicant’s position that the claimed invention encompasses performance of the method using any known neo-epitope antibody for C3a or C5a known in the art, that it is suggested that Applicant amend the claims in order to omit the functional language. Applicant’s arguments at remarks page 9, that Applicant was in possession because the single disclosed species is representative of the entire claimed genus because the skilled artisan would understand that a neo-epitope antibody which binds with the claimed properties would allow for measuring activity as claimed is also not persuasive because the claimed invention is not, for example, merely limited to any known neo-epitope antibody, but rather only those exhibiting the required functional limitations.
Regarding remarks pages 9-10, Applicant citing Appendix B to support that antibodies that are anti-C3a and anti-C5a neo-epitope antibodies were well known in the art and commercially available, however Appendix B is not sufficient to overcome the rejection because it is not evidence that any and all neo-epitope antibodies that bind C3a and C5a exhibit the claimed functional limitations.
At remarks pages 10-11 Applicant further agues the claimed methods are drawn to methods not a composition of matter. However, while the use of the antibody is just one part of the claimed method, it is an essential part of the claimed methods int that it allows one practicing the method to ascertain activity. Thus, the issue to consider is whether Applicant has described the claimed antibodies in such terms as to convey to one skilled in the art that the inventors had in their possession the broadly claimed genus. See the factors as cited in detail in the rejection above, the totality of evidence does not support Applicant was in possession of the entire genus as claimed in terms of functional terms.
Similarly, regarding remarks at page 11-12, specific to the new limitations “means for binding”, these claims are not rejected (see as at the pending rejection above), as these claims are not limited, for example in terms of the functional language as recited at the rejected claims.
Regarding remarks at page 12, see as indicated in detail above, the previous rejection of claims under 35 U.S.C. 112(b) is withdrawn in response to Applicant’s amendments to the claims.
At remarks pages 12-21 Applicant argues the rejections of claims under 35 U.S.C. 103(a), specifically that the combination of the cited fails to teach or suggest immobilizing with biotin and detection with neo-epitope antibody having a high affinity for C3a and low affinity for C3 as claimed using a MSD-ECL immunoassay.
Applicant argues that each of the cited references fails to teach particular limitations specific to the claims (page 14, that Krych-Goldbert does not teach measuring C3 convertase activity using MSD, nor use of neo-epitope antibody; that Eberhardt merely teaches biotinylated C3b immobilized on a sensor that is an SPR sensor; page 15, that Opperman discloses quantitation of C5a/C5a(desArg) in human plasma, and does not teach neo-epitope anti-C5a antibody in an in vitro assay to measure C5 convertase as claimed).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The rationales to combine are as set forth in detail above in the rejections.
Further, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning (remarks page 15), it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). It is maintained that the pending grounds of rejection only take into account knowledge within the level of ordinary skill.
Applicant further argues (remarks page 15-16) that the rationale to combine is that one would have been motivated have substituted the assay of Eberhardt into Krych-Goldberg’s system.
However, this is not the case, see as cited in the detailed rejection above, Krych-Goldberg et al. fails to teach the C3b dimer is covalently attached to a tag comprising biotin or an analog or derivative thereof (claim 48). Krych-Goldberg et al. is also silent as to whether or not the C5 convertase assay, similar to the C3 convertase assay, detects generation of the cleavage product that results. Put another way, Krych-Goldberg is silent as to whether immunoassay is performed in order to detect C5a.
Eberhardt et al. teach an example of immobilization of C3b to a solid phase substrate, see Eberhardt et al. teach N-biotinylated C3b bound at a sensor chip surface by way of streptavidin (streptavidin coated surface used to bind the biotinylated C3b, page 2, last paragraph at col. 1).
The position set forth in the rejection is that it would have been prima facie obvious to have coated the C3b to the solid support (the microtiter plate) by way of biotin-streptavidin binding (i.e. covalent binding of biotin to the biotin binding protein streptavidin), as in Eberhardt et al. as an obvious matter of applying a known technique to a known method (meaning a known technique for immobilizing/attaching this particular reagent at a solid support surface).
Then subsequently in addition to this rationale noted above, it was also indicate that because both techniques for providing C3b coated surface were known in the art (see it was known that one could coat a surfaces as in Krych-Goldberg or coat a surface using biotin-streptavidin binding at the surface), it also would have been an obvious matter of a simple substitution of one know technique for providing C3b at a solid support surface for another. Further, because both were known ways of providing C3b at the solid support surface, one would have a reasonable expectation of success substituting one for the other.
As a result, in order to clarify in response to remarks at page 15, the rationale is not that it would have been obvious to have modified Krych-Goldberg in order to substitute the assay of Eberhardt.
Regarding remarks asserting the Office has applied improper hindsight reasoning (remarks page 16), this argument is as addressed previously above.
At remarks page 16-18, Applicant argues the citation of the additional cited art addressing further dependent claims does not cure deficiencies as asserted above. However, regarding arguments specific to the independent claims, see the response as indicated in detail above.
Regarding the claims 61 and 62 directed to claims, referring arguments presented at pages 19-20, Applicant argues each reference individually. As noted above, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The combined prior art teach kits as presently claimed.
For all of these reasons, Applicant’s arguments are not persuasive.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
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/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677
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