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 .
Priority
The present application was filed as a proper National Stage (371) entry of PCT Application No. PCT/EP2019/077971, filed 10/15/2019. Acknowledgement is also made of applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. EP182000435.8, filed on 10/15/2018 in Europe.
Status of the claims
Claims 1, 3-9, and 16 are pending, claims 2, 10-15 are cancelled. Claim 16 is new. Claims 1, 3-9, and 16 are examined below.
Withdrawn rejection
The rejection of claims 2 and 3 under 35 U.S.C. 112(b) has been withdrawn due to the cancellation of claim 2 and the amendment of claim 3.
The rejection of claims 1, 3-9, and 16 under 35 U.S.C. 112(b) regarding the C-peptide variants has been withdrawn in view of Applicant’s amendment and/or arguments.
Drawings
The drawings are objected to for reasons of record. Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Rejections - 35 USC § 112, paragraph (a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-9, and 16 are rejected for reasons of record which are reiterated herein below.
Claims 1, 3-9, and 16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1 and 8-9 recite an antibody that has certain desired properties, namely “an antibody directed against C-peptide,” wherein the antibody must bind with higher affinity to wild type C-peptide and with lower affinity to a ligand. However, neither the claims nor the specification disclose the structure of an antibody that has this particular function. The claims encompass a large genus of products that may be characterized by substantial variability. The claims place no limitations on the sequence/structure of the antibody itself, and rather define the antibody only in term of desired binding properties.
The claim scope is potentially enormous depending on how many of the products that meet the structural requirements also meet the functional requirements (i.e. being directed against C-peptide). Furthermore, the specification fails to disclose sufficient identifying characteristics of the genus (the claimed antibody), as discussed in more detail below, such that one having ordinary skill in the art can readily visualize the species encompassed by the claimed genus (i.e., what antibodies meeting the structural requirement also exhibit the required functional, namely binding, requirement).
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). 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.
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. Regents 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).
In the present case there is insufficient evidence of such an established structure-function correlation in the case of antibodies directed against C-peptide, whereby the antibodies bind with lower affinity to a ligand than to wild type C-peptide.
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).
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. The original specification discloses only 6 commercially available anti-human C-peptide antibodies and does not identify with any particularity any other antibodies that could be used (Specification, page 3, lines 19-27).
The art recognizes that structure (of a particular antigen) is not necessarily a reliable indicator of function, so even if the claim was reciting a particular antigen sequence to which the antibody binds, there still may be insufficient written description to support the entire genus as claimed.
The teachings of Harlow, 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).
The principles laid out in Harlow are further illustrated in the teachings of Edwards et al. ("The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BLyS" J. Mol. Biol. (2003) 334, pages 103–118), which shows the immense combinatorial flexibility and capacity of the human antibody repertoire to generate binding sites to an individual protein antigen, the B-lymphocyte growth factor known as “BLyS” (see entire document). Edwards describes in detail how the breadth of antibody structures against a given immunogen can be influenced by the immunization and/or selection methods (see Discussion Section).
Like Edwards, Lloyd et al. ("Modelling the human immune response: performance of a 1011 human antibody repertoire against a broad panel of therapeutically relevant antigens", Protein Engineering, Design and Selection, Volume 22, Issue 3, 1 March 2009, Pages 159–168) shows a repertoire of 1x1011 human antibody variable regions can generate large numbers of unique, biologically active scFvs against a variety of polypeptide targets (see e.g., at page 161-62 bridging paragraph and in Table 1, cited herewith).
As yet another example to illustrate the potential scope of the genus of antibodies encompassed by the instant claims, consider the teachings of Meyer et al. (“New Insights in Type I and II CD20 Antibody Mechanisms-Of-Action With a Panel of Novel CD20 Antibodies”, British Journal of Haematology, 2018, 180, 808–820). Meyer describes the core binding region of the well-known anti-CD20 antibody rituximab corresponds to amino acid residues 170ANPS173, wherein N171 is the key residue for binding. By contrast, the OBZ and B1 anti-CD20 antibodies share an overlapping epitope with rituximab (170ANPSEKNSP178); however, in contrast to rituximab residues at positions 176–178 contribute the most to binding (see page 809, left col., 2nd full paragraph).
Meyer also described the production and characterization of a panel of new anti-CD20 antibodies which were shown to bind epitopes contained within or nearby the rituximab 170ANPS173 epitope but to bind to different residues than rituximab binds in this region (see page 811, “New CD20 mAbs with overlapping, but distinct epitopes,” see also page 815-16 bridging paragraph).
More particularly, Meyer teaches the newly created anti-CD20 mAbs m1 and m2 were found to bind within but also in the vicinity of the rituximab binding site (m1 and m2) and elsewhere (m2): “detailed epitope mapping was performed for both mIgG2c-CD20 mAbs m1 and m2, by using PepScan technology. We identified the critical residues of m1 to be 168EPANPSEK175 by using linear (Figure S2A) and circular (Fig 2C, left) peptides with a positional amino acid scan covering the larger extracellular loop. Also for m2, a signal decrease below the WT binding signal occurred within the 168EPANPSEK175 sequence motif but the binding signal to the linear (Figure S2B) and circular (Fig 2C, right) peptide was rather low. This suggests that the epitope of both mAbs is located on the larger loop in the same region, however their binding characteristics are different. The data suggests that m1 binds a linear epitope, whereas m2 binds to a conformational epitope.” (see ibid). Moreover, while these antibodies bind within or nearby the rituximab 170ANPS173 epitope they do so with heavy and light chain CDRs non-homologous to those of rituximab. Thus, even if multiple antibodies bind epitopes within the same small region of a given polypeptide it is not uncommon for said antibodies to bind to different amino acids even within said small region and for said antibodies to have structurally dissimilar CDRs.
Vajdos et al. (Vajdos et al. (2002) "Comprehensive functional maps of the antigen-binding site of an anti-ErbB2 antibody obtained with shotgun scanning mutagenesis", Journal of molecular biology, 320, 2, pages:415-428) teaches 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 visualize or recognize the identities of the members of the claimed genus that exhibit this functional property (an antibody directed against C-peptide whereby the antibody binds with lower affinity to a ligand than to wild type C-peptide). As supported by the above cited evidence, even knowing the structure of the antigen one cannot readily visualize structure specific for the binding agent that binds the antigen because the structure is not necessarily a reliable indicator of function. In the instant case, there is no clear structure-function correlation to allow the ordinary skilled artisan to readily envision what species are encompassed by the claimed genus. There is insufficient written description to support that Applicant was in possession of all antibodies capable of binding a ligand with lower affinity than wild type C-peptide. Additionally, the characteristics defining the genus of antibody that is “directed against C-peptide” is 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.
Regarding Applicant’s actual reduction to practice, the specification discloses (page 3, lines 19-27) six commercially available anti-human C-peptide antibodies and further discloses that an antibody with high affinity to the target analyte C-peptide can be used (page 6, lines 1-2) the specification does not identify with any particularity any other antibodies that could be used and only describes the antibodies by their function.
The specification fails to provide adequate written description for the genus of antibodies claimed, as the antibodies are described only in terms of desired functional properties and not in terms of common structure or other relevant identifying characteristics to define the genus and there is no apparent structure-function correlation which would allow one to readily visualize what species would and would not be encompassed by the claimed invention. 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.
Claims 3-7 and 16 depend on claim 1 and are therefore also rejected.
Claim Rejections - 35 USC § 112, paragraph (b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 8 and 9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 8, the claim recites “contacting the antibody with a ligand”. The claim language is indefinite because it is unclear whether or not the ligand recited in claim 8 is the same ligand recited in claim 1.
Regarding claim 9, the claim recites “immobilizing a ligand on the solid phase”. The claim language is indefinite because, similarly to claim 8, it is unclear whether or not the ligand recited in claim 9 is the same ligand as recited in claim 1.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-9, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Ligler et al., US 5,354,654, granted 10/11/1994 (PTO-892, 06/14/2024) in view of Ngo (2005) “Ligand Displacement Immunoassay”, Analytical Letters, 38, 7, pages 1057-1069 (IDS 04/12/2021) and Wahren et al., WO2005118638A1 (PTO-892, 01/09/2024).
Regarding claim 1, 3-5, and 16, Ligler teaches a method comprising a displacement assay comprising binding a labelled ligand or a labelled receptor to an immobilized receptor or ligand to obtain an immobilized ligand-receptor complex (Ligler, especially at column 3, lines 16-39) for biomolecules including C-peptide (Ligler, column 6, line 10; claim 15). Ligler further teaches that the ligand-receptor pair may comprise antibody-antigen or hapten (Ligler, column 5, lines 32-35), meaning that the immobilized ligand-receptor complex is an antibody-ligand-complex as claimed instantly (see also claim 13).
Ligler further teaches that the labelled ligand or receptor may be the identical molecule as the analyte or may be structurally distinct from the analyte, so long as it and the analyte both bind specifically to the immobilized receptor or ligand (Ligler, column 7, lines 23-29).
Ligler further teaches that the sample containing the analyte is passed through a column containing a labelled ligand-immobilized receptor complex and the amount of labelled ligand displaced by the analyte is detected in the liquid phase exiting the column (Ligler, column 10, lines 9-15). This allows indication of the presence of the target analyte, which again may be C-peptide (see also column 10, lines 34-41).
Ligler does not teach that the ligand has a lower affinity to the anti-C-peptide antibody than wild type C-peptide. Ligler further fails to teach that the ligand is a C-peptide variant of the wild-type C-peptide of SEQ ID No: 1 comprising the amino acids between positions 8-17 of SEQ ID NO:1, and comprising a substituted amino acid at 12 (L).
Ngo teaches that in displacement assays, the antibody with the highest binding constant may not be the best for an assay with greatest sensitivity, because it makes the displacement of labeled antigen to the antibody by analyte antigens much more difficult and requires higher concentrations of antigen, rendering the assay less sensitive (Ngo, page 1060, lines 9-15). Ngo further teaches that antibodies with weaker affinity for the labeled antigens can be used or cross -reactive antibodies can be used that have greater affinity with analyte antigens than with the labeled antigens (Ngo, page 1060, lines 16-21).
Wahren teaches providing modified variants or analogues of C-peptide which have been modified to increase the in vivo half-life of C-peptide so as to provide a longer-lasting and more efficacious therapeutic agent, because a treatment with longer lasting action can be administered less often and would be of great clinical importance and utility (Wahren, page 7, see paragraph 1). Wahren further teaches that human C-peptide is a 31 amino acid peptide having the following sequence: EAEDLQVGQVELGGGPGAGSLQPLALEGSLQ (SEQ ID No: 1 of Wahren), the sequence being identical to that of SEQ ID No: 1 of the present application (Wahren, page 4, 3rd paragraph). Wahren further teaches that C-peptide is known to have a relatively short half-life. Wahren teaches that the peptides may be in their native form or may be truncated (e.g. from the N- or C-terminus or both (claim 4; Wahren, page 9, lines 9-15). As such Wahren teaches a C-peptide variant, wherein amino acids 1-20 are deleted at the C- and/or N-terminus as recited in claim 4 of the present application. Wahren teaches that the substituted acid can be one of the well-known 20 conventional amino acids, comprising Cysteine (C) (instant claims 3, 5, and 16; Wahren, page 11, lines 14-16). Wahren teaches that the analogue may be modified at any one or combination of the leucine residues at positions 5, 12, 21, 24, 26, or 30 (12(L), ( Wahren, page 19, see 4th paragraph, lines 1-3; claims 1 and 6-9). Wahren teaches that C-peptide starts to degrade in as little as 15-20 minutes in an in vitro assay (Wahren, page 33, lines 6-9). Wahren teaches that C-peptide analogues show increased half-life of 20-35% in the in vitro assay (Wahren, page 37, see 2nd paragraph). Wahren teaches that it is important that the C-peptide analogues retain C-peptide activity (Wahren , page 15, 2nd paragraph, lines 1-2) and that affinity tests based on measurements of protein binding may be used as activity tests of C-peptide (Wahren , page 17, lines 10-12).
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 method of Ligler of detecting analyte in the liquid phase exiting the column, with the method of Ngo, measuring the concentration of the displaced labeled antigen, because by measuring the displaced antigens and using a standard calibration curve, one can determine the concentration of the antigens in the test sample.
The artisan would have had a reasonable expectation of success in determining the amount of displaced ligand as evidenced by Ligler’s Figures 1-2, which show that the assay was sensitive to changes in target analyte concentration.
It would have further 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 method of Ligler in view of Ngo, a displacement assay for the detection of C-peptide, wherein the ligand and the analyte both bind specifically to an immobilized antibody and the antibody binds with greater affinity to the analyte then the ligand, to arrive at the claimed C-peptide ligand with a substitution of the leucine residue at position 12 with cysteine, because Wahren teaches that the C-peptide analogues can be modified at any one or combination of the leucine residues at positions 5, 12, 21, 24, 26, or 30 and that the substitutions can be one of the well-known 20 conventional amino acids. Specifically, the combination would have been an obvious matter of selecting a substitution from the finite list of suitable alternatives, to arrive at a peptide comprising the C-peptide of SEQ ID No: 6, which is amino acids 8-17 of SEQ ID NO. 1 with a substitution of L(12) to C (SEQ ID No: 6 being applicant’s elected species), as claimed. See MPEP 2143 (I)(E). The ordinary artisan would have been motivated to do so, because of the teaching of Wahren that a substitution of the leucine residues, including the leucine residue at position 12 increases the stability of the C-peptide analogue and that the substitution comprises one of the well-known 20 amino acids, which include cysteine. Wahren teaches increased stability in an in vitro assay, while the native C-peptide starts being degraded within only 15-20 min.
The ordinary artisan would have a reasonable expectation of success, because Ligler teaches a method of detecting C-peptide in a displacement assay, where the displaced ligand can be structurally distinct form the analyte, for example C-peptide, as long as it binds specifically to the immobilized receptor and Wahren teaches modified C-peptide variants that retain affinity in a protein binding assay.
Regarding claim 6, Ligler teaches a labelled ligand or a labelled receptor in an immobilized ligand-receptor complex (Ligler, column 3, lines 37-40).
Regarding claim 7, Ligler teaches the label can be a fluorophore, a chromophore, a radiolabel, a metal colloid, and enzyme, or a chemiluminescent or bioluminescent molecule (Ligler, column 7, lines 39-42).
Regarding claims 8 and 9, Ligler and the cited art above teach a method comprising a displacement assay substantially as claimed.
Ligler teaches a support for the immobilized receptor or ligand that may be composed of glass, silicon, quartz, paper, nitrocellulose, or polymers (Ligler, column 8, lines 4-6). Ligler further teaches that the ligand-receptor pair may comprise antibody-antigen or hapten (Ligler, column 5, lines 32-35). Ligler further teaches that a labelled ligand or a labelled receptor is bound to an immobilized receptor (instant claim 8) or an immobilized ligand (instant claim 9; Ligler, column 4, lines 21-35). Ligler further teaches that the sample containing the analyte is passed through a column containing a labelled ligand-immobilized receptor complex and the amount of labelled ligand displaced by the analyte is detected in the liquid phase exiting the column (Ligler, column 10, lines 9-15). Ligler further teaches detecting biomolecules including C-peptide (Ligler, column 6, line 10).
Ligler fails to teach determining the amount of displaced ligand, as in claim 8 f).
Ngo teaches that the presence of antigens in a test sample will displace the bound labeled antigens from the immobilized antibodies and that the amount of displaced labeled antigens is proportional to the amount of antigens present in the sample. Ngo further teaches that by measuring the concentration of labeled antigens displaced and using a standard calibration curve, the concentration of the antigens in the test sample can be determined (Ngo, page 1057, ‘Introduction’, lines 3-8).
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 method of Ligler of detecting analyte in the liquid phase exiting the column, with the method of Ngo, measuring the concentration of the displaced labeled antigen, because by measuring the displaced antigens and using a standard calibration curve, one can determine the concentration of the antigens in the test sample.
The ordinary artisan would have had a reasonable expectation of success in determining the amount of displaced ligand as evidenced by Ligler’s Figures 1-2, which show that the assay was sensitive to changes in target analyte concentration.
Response to Arguments
Applicant's arguments filed 05/06/2025 have been fully considered but they are not persuasive.
Applicant argues on page 5 that no drawing in color was found in the application. However, the objection of the drawings is upheld, because even though black and white copies of the drawings have been filed, the original filing of 04/12/2021 also comprises color drawings.
Applicant further argues, starting on page 5 that the amended claims are supported by the written description and that the specification provides detailed, representative examples of the claimed ligand variants, demonstrating that the inventor had possession of the claimed subject matter. After further consideration the rejection under 35 U.S.C. 112(a) regarding the C-peptide variants has been withdrawn.
However, the rejection of claims 1, 3-9, and 16 under 35 U.S.C. 112(a) regarding the antibodies directed against C-peptide has been maintained because the claims lack written description in regards to the “antibody directed against C-peptide” which is described entirely by certain desired properties and not by structure. As discussed previously above, this results in a potentially enormous claim scope without description of any identifying characteristics and therefore one having ordinary skill in the art cannot readily visualize the species encompassed in the claimed genus.
Applicant further argues, starting on page 6, that Ligler and Ngo fails to teach all of the requirements of the amended claims.
Applicant further argues that the cited references fail to teach or suggest a method utilizing a ligand which is a C-peptide variant of the wild-type C-peptide and further fail to teach or suggest a method utilizing a ligand which has a lower affinity to anti-C-peptide antibody than wild type C-peptide as required by the pending claims. However, as explained previously in detail above, the combination of the art of Ligler in view of Ngo and Wahren renders the method obvious.
Specifically, applicant argues that Ligler refers to displacement assays in general and that C-peptide specifically is only mentioned in an expansive list. However, the list provides a finite number of specific targets the displacement assay can be applied to and therefore the argument is not persuasive. Applicant further argues that Ligler does not teach the use of a “variant” peptide and the person having ordinary skill in the art would not be motivated to utilize a ligand that is a C-peptide variant. Ligler also fails to teach a ligand that has lower affinity to anti-C-peptide antibody than wild type C-peptide and teaches a ligand with the same affinity as the analyte. However, Ligler is relied on to teach the displacement assay including an embodiment where the analyte is C-peptide. Ligler is not relied on to teach a C-peptide variant, rather Wahren is relied on to teach a c-peptide variant and Ngo is relied on to teach a ligand in a displacement assay that has lower affinity than the analyte. Therefore the argument is not persuasive.
Applicant further argues that Ngo is not relied on to supply the missing teaching. However, as explained previously in detail above, Ngo is relied on to teach a peptide with lower affinity than the analyte.
Applicant further argues that that Wahren teaches degradation-resistant analogues of pro-insulin C-peptide which have increased resistance to proteolytic degradation as compared to non-modified C-peptide, but does not teach C-peptide variants with a lower affinity to anti-C-peptide antibody than wild type C-peptide. However, Wahren teaches a C-peptide with a sequence identical to that of applicant’s elected species and as such teaches a peptide with lower affinity to anti-C-peptide antibody.
For all the reasons above the arguments are not persuasive.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Communication
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/STEFANIE J. KIRWIN/Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 September 29, 2025