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 01/28/2021 and claims benefit under 35 U.S.C. 119 (e) to provisional application No. 62/968, 637, filed on 01/31/2020.
Status of the Claims
Claims 1-18, 21-22, 25-29, and 31-35 are pending. Claim 18 is amended. Claims 1-17 are withdrawn. Claims 19-20, 23-24, and 30 are cancelled. Claims 18, 21-22, 25-29, and 31-35 are pending and examined below.
Withdrawn objections
The objection to claim 18 is withdrawn due to the amendment of the claim.
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.
The rejection of claims 18, 21-22, 25-29, and 31-35 is maintained for reasons of record and reiterated below:
Claims 18, 21-22, 25-29, and 31-35 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.
Claim 18 recites “antibodies which are derived from and specifically binds to human proUGN” and “the first and second antibodies include one or more amino acid sequence complementary to one or more portion of SEQ ID NO: 1, 2, 3, or 4”. Claim 18 therefore, encompasses a large genus of products that may be characterized by substantial variability. The claim language places no limitations on the sequence/structure of the antibody itself, and rather defines the antibody only in terms of desired binding properties (i.e., the residues to which it binds, not structure specific to the antibody itself).
The claim scope is potentially substantial depending on how many of the products that meet the structural requirements would also meet the functional requirements (i.e., being derived from and specifically binding to human proUGN, encoded by SEQ ID NO:1). 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).
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, however, there is insufficient evidence of such an established structure-function correlation in the case of “antibodies being derived from and specifically binding human proUGN”. While the claims recite “antibodies being derived from and specifically binding”, it is noted that applicant appears to merely mean antibodies specifically binding human proUGN.
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).
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.
While in the present case the specification discloses how to make a monoclonal antibody, the specification fails to disclose any particular species such that a structure-function correlation can be determined/visualized (i.e., such that one can visualize what structural feature is required of all antibodies, that all antibodies must possess, in order to achieve binding as claimed). The claims are limited to antibodies that “are derived from and specifically bind to human proUGN” (as explained previously above, this appears to merely mean antibodies that are specific for/bind to human proUGN), nonetheless, even limited to a particular antigen structure, the art recognized structure (of a particular antigen) is not necessarily a reliable indicator of function, so even claims reciting a particular amino acid sequence/epitope to which the antibodies bind do not necessarily establish sufficient support of an entire genus as claimed.
The teachings of Harlow et al. (Antibodies, A Laboratory Manual, Cold Spring Harbor laboratory, 1988, pages 25-26 and 37-59, cited herewith; see PTO-892 06/24/2024) 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, 103–118, DOI: 10.1016/j.jmb.2003.09.054; see PTO-892 06/24/2024), 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).
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, |https://doi.org/10.1111/bjh.15132; see PTO-892 06/24/2024). 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, such as the N- or C-terminal regions of pro-UGN (as claimed in claim 27), much less the full polypeptide of proUGN, it is not uncommon for said antibodies to have structurally dissimilar CDRs. As such, one cannot readily predict which antibodies in terms of their structure would bind the claimed region.
One cannot readily visualize or recognize the identities of the members of the claimed genus that exhibit these functional properties (antibodies that are specific for human proUGN). The specification does not identify what particular epitopes the binding agents bind to, and as supported by the above cited evidence, even knowing the structure of the antigen one cannot readily visualize structure specific to the antibody 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 an epitope as claimed, considering based on a review of the specification, the epitope was apparently not yet defined at the time of filing (however, as noted above, even if the epitope was known, this would be structure specific to the antigen not the claimed antibodies). 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 recites the practice for how to develop monoclonal antibodies specific to proUGN (e.g., see Example 2 of the specification), namely immunizing laboratory mice with recombinant human protein, peptides conjugated to a carrier protein, plasmids able to express full-length and fragments thereof of the protein, or combinations of these antigen or antigen sources (paragraph [0084]). The specification further recites immortalizing B cells to reproducibly generate proUGN specific antibodies (paragraph [0085]). Such a plan set forth in order to produce specific antibodies does not allow one to envision the structure of (or any structure specific to) the antibodies that are claimed.
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, 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.
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.
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.
The rejection under 35 U.S.C. 112(b) is maintained for the reasons of record and reiterated below:
Claims 18, 21-22, 25-29, and 31-35 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 18, the claim recites “antibodies which are derived from and specifically bind to human proUGN”. The claim language is indefinite, because it is unclear what applicant means by “derived from […] human proUGN”. Merriam-webster defines “derive” as (a) “to take, receive, or obtain especially from a parent substance” and (b) to obtain (a chemical substance) actually or theoretically from a parent substance” (https://www.merriam-webster.com/dictionary/derive; accessed 02/06/2025). Further, on page 25, paragraph [0069] of the specification of the present application, applicant recites that “The term “antibody” as used herein refers to a peptide or polypeptide derived from, modeled after or substantially encoded by an immunoglobulin gene or immunoglobulin genes, or fragments thereof, capable of specifically binding an antigen or epitope.” Human proUGN is not an immunoglobulin gene nor is the antibody obtained from proUGN as the parent substance and it is therefore unclear what applicant means by describing the antibody as derived from human proUGN.
Claim 18 further recites “one or more amino acid sequence complementary to one or more potion of SEQ ID NO:1, 2, 3, or 4”. Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “complementary” in claim 18 appears to be used by the claim to mean “an amino acid sequence capable of binding another amino acid sequence,” while the accepted meaning is “the complementarity of base sequences in nucleic acids with adenine complementary to thymine and guanine complementary to cytosine”, see for example Travers A, Muskhelishvili G. DNA structure and function. The FEBS journal. 2015 Jun;282(12):2279-95, page 2279, 2nd paragraph, lines 4-8. The term is indefinite because the specification does not clearly redefine the term.
In the interest of compact prosecution “antibodies which are derived from and specifically bind to human proUGN” and “antibodies include one or more amino acid sequence complementary to one or more portion of SEQ ID NO:1, 2, 3, or 4” will be interpreted as antibodies specifically binding to one or more portions of SEQ ID NO:1, 2, 3, or 4.
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 18, 21-22, 25-26, and 31-34 are rejected under 35 U.S.C. 103 as being unpatentable over Di Guglielmo et al. (2018) “Pilot Study Measuring the Novel Satiety Hormone, Pro-Uroguanylin, in Adolescents With and Without Obesity”, Journal of Pediatric Gastroenterology and Nutrition, 66, pages 489-495 (see PTO-892, 06/23/2023), as evidenced by BioVendor “Human Prouroguanylin ELISA” Product Data Sheet, Cat. No.: RD191069200R (obtained at www.biovendor.com/file/5051/PDS_35_HPUGE_ENG.005.A.pdf, pages 1-24 (see PTO-892, 06/23/2023), in view of Goy et al. WO2006001931A2 and Payne et al. (1988) “Clinical laboratory applications of monoclonal antibodies, Clinical Microbiology Reviews, 1, 3, pages 313-329 (see PTO-892, 06/23/2023).
Regarding claims 18 and 31, Di Guglielmo teaches an ELISA kit (human pro-uroguanylin ELISA, BioVendor) with a microplate well coated with polyclonal antihuman pro-uroguanylin antibody (antibody adhered to solid phase support) and a biotin-labeled polyclonal anti-human pro-uroguanylin antibody (second antibody comprising a detectable marker; at least one of the first and second specifically bind to human proUGN; complementary to one or more portion of SEQ ID NO:1, 2, 3, or 4, SEQ ID NO:1 being human proUGN; Di Guglielmo, page 490, col. 2, ‘Sample Processing […]’, lines 5-12).
Regarding the quantitative sandwich ELISA kit from BioVendor (Brno, Czech Republic), see as evidence, the BioVendor, Human Prouroguanylin ELISA kit (hereinafter referred to as the BioVendor ProUGN datasheet) product data sheet reciting “The severity of chronic renal disease correlated with the magnitude of increases in plasma pro-uroguanylin concentrations.” The BioVendor ProUGN data sheet associated with the ELISA referred to in Di Guglielmo lists instructions and reagents (BioVendor, page 4, lines 5-7, see also page 10, Assay procedure), the kit is comprising instructions on how to measure pro-uroguanylin levels (BioVendor, page 9, see ’11. Assay Procedure’) these instructions (see per the datasheet) teaching severity of the disease correlates with increase of plasma pro-uroguanylin, the kit therefore includes instructions on how to carry out the diagnosis of renal dysfunction or disease, as claimed. The BioVendor ProUGN data sheet further teaches that Prouroguanylin levels are markedly increased in chronic renal failure and that the severity of chronic renal disease correlates with the magnitude of increases in plasma prouroguanylin concentrations (chronic kidney disease; BioVendor, page 4, ‘3. Introduction’, see 2nd paragraph).
Although the kit as taught by Di Guglielmo does provide instructions consistent with those claimed (as is evidenced by BioVendor ProUGN datasheet), see further MPEP 2112.01 regarding printed matter and “instructions” limitations. The inquiry for product inventions containing such limitations, is whether there is a new and nonobvious functional relationship with product and the printed matter. In the present case, no such new or non-obvious functional relationship with the kit components exists, especially considering the evidence further supports that the kit (of the cited art) was intended for the same purpose (for relating the measured level with chronic renal failure, see as evidenced by BioVendor).
Di Guglielmo does not teach monoclonal first and second pro-uroguanylin antibodies. Di Guglielmo further fails to specifically teach that the antigen which the antibodies are specific for, is secreted by a human kidney cell.
Goy teaches an immunoassay kit for detecting a level of pro-uroguanylin in a sample and further a method for determining the presence of progression of a disorder characterized by salt retention, fluid retention, salt loss, fluid loss, and a combination thereof (Goy, see entire Abstract). Goy further teaches that kidney disease is one disease associated with sodium retention (Goy, page 4, lines 19-21). Goy further teaches two antibodies against two regions of rat pro-uroguanylin (Goy, page 35, lines 26-27). Goy further teaches that biological samples were fractionated by SDS-PAGE prior to performing immunoassays to ensure that all molecular species detected had a molecular weight corresponding to full-length pro-uroguanylin, eliminating antibody cross-reactivity with pro-uroguanylin cleavage products or other irrelevant proteins (Goy, pages 34-35, lines 33-4). Goy further teaches that in some embodiments, the anti-prouroguanylin antibodies provided for the immunoassays are polyclonal antibodies (Goy, page 31, lines 7-9). Goy further teaches that monoclonal antibodies can also be used and that monoclonal antibodies can be produced from the epitopes described for anti-proUGN antibodies (Goy, page 32, lines 1-3). Goy teaches the sequence of human prouroguanylin (SEQ ID NO: 5; Goy, page 12, lines 28-30). Goy further teaches that the immunogen of interest is a portion of the prouroguanylin peptide distinct from the amino acid sequence of UGn18 in rats and UGn16 in humans (Goy, page 31, lines 13-15). Goy further teaches that the hybridoma from which the monoclonal antibody composition is produced is fused with lymphocytes obtained from the spleen of a mammal hyperimmunized with antigen comprising a proUGN epitope (Goy, page 32, lines 13-16). Goy further teaches that the invention pertains to human patients and that measuring the plasma levels of endogenous pro-uroguanylin is of diagnostic value in evaluating the status of patients with diseases such as kidney disease (Goy, page 10, lines 23-31). As such, Goy teaches a kit for detecting pro-uroguanylin in human samples using two monoclonal antibodies specific for different regions of full length pro-uroguanylin.
Payne teaches that the major advantages of monoclonal antibodies in an immunoassay are their specificity and the consistency of the supply of reagent (Payne et al., page 320, lines 8-9). Payne further teaches that for example using monoclonal antibodies to detect rotavirus, the monoclonal antibodies show higher sensitivity and specificity than polyclonal antibodies (Payne page 321, lines 2-4). Still further, Payne teaches that monoclonal antibodies are excellent tools for identifying antigens (Payne, page 321, lines 8-9). Still further, Payne et al. teaches that in immunodiagnosis using ELISA, monoclonal antibodies have improved assay specificity and have helped eliminate cross-reactivity problems frequently encountered with polyclonal reagents (Payne, page 321, ‘ELISA’, ‘Mab application for Immunodiagnosis’, lines 4-8).
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 kit of Di Guglielmo et al. to use monoclonal anti-progurouanylin antibodies that have been evaluated by SDS-PAGE, such as the antibodies taught by Goy. One of ordinary skill in the art would be motivated to do so because of the teaching of Goy, that the antibodies are specific only for full length pro-uroguanylin and not cross-reactive with any degradation product or irrelevant antigen and because of the teaching of Payne et al. that monoclonal antibodies have improved assay sensitivity and specificity and that they help eliminate cross-reactivity frequently encountered with polyclonal reagents.
One of ordinary skill in the art would have a reasonable expectation of success in having modified the kit of Di Guglielmo with the monoclonal antibody of Goy, because Goy teaches detecting human proUGN using specific antibodies in an immunoassay to diagnose kidney disease, as does Di Guglielmo.
Further, regarding the limitation wherein the antibody specifically binds to “human proUGN, or a fragment or post-translational modification thereof […] secreted from a human kidney cell”, the limitation is addressed by the prior art, because Goy teaches evaluating antibodies by SDS-PAGE to ensure that the antibodies are specific only for full-length pro-uroguanylin and not cross-reactive with any degradation product or irrelevant antigen. As such structurally the prior art is indistinct from the product claimed. “Secreted from a human kidney cell” is a limitation that describes how the product is made. This is a product by process type claim limitation and “even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. […] If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). See MPEP 2113. In the present case, the prior art is teaching antibodies that specifically bind to human proUGN secreted from a human kidney cell, or a fragment or post-translational modification thereof, so it reads on the claim.
Regarding claim 21, Di Guglielmo et al. as evidenced by BioVendor teaches the kit as claimed, namely the ELISA comprising a dilution buffer (sample buffer) and a wash solution concentrate (wash buffer; BioVendor, page 6, see Kit components).
Regarding claim 22, Di Guglielmo et al. as evidenced by BioVendor teaches the kit comprising a second antibody with a detectable marker, the marker being Horseradish peroxidase (enzyme) and a substrate solution (BioVendor, page 6, see Kit components).
Regarding claims 25-26, Di Guglielmo et al. teaches a kit with microplate wells (solid phase support; multi-well plate) coated with antihuman proUGN antibody (Di Guglielmo et al., page 490, ‘Sample Processing […]’, lines 9-10).
Regarding claim 32, Di Guglielmo et al. in view of the prior art above teaches a kit comprising monoclonal antibodies used to measure human pro-uroguanylin levels in freshly thawed human plasma (Di Guglielmo et al., page 490, ‘’Sample Processing and Assay Methods”, lines 1-7).
As previously discussed in detail above, Goy discloses that all molecular species detected by the antibodies had a molecular weight corresponding to full-length pro-uroguanylin (Goy, pages 34-35, lines 33-4). Goy further teaches that the antibodies detects pro-uroguanylin from tissue samples of rat small intestine (Goy, page 36, lines 16-18). Goy further teaches that the invention pertains to human patients (Goy, page 10, lines 23-31). Put another way, Di Guglielmo in view of Goy teaches an immunoassay kit comprising antibodies specific for full length pro-uroguanylin protein derived from mammalian cells, i.e. post-translationally modified.
Regarding claim 33, Di Guglielmo teaches kits for measuring GLP-1, IL-6, PYY, ghrelin, and CRP levels by ELISA (Guglielmo, see page 490, last paragraph- page 491, line 1), and as such further teaches a third antibody adhered to a surface and a fourth antibody comprising a detectable marker (as required for an ELISA assay, comprising a plate bound capture antibody and a labeled detection antibody, see above as evidenced by the BioVendor kit).
Regarding claim 34, Di Guglielmo teaches a kit for a second biomarker, which is IL-6.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Di Guglielmo (as evidenced by BioVendor), in view of Goy and Payne as applied to claim 18 above, and further in view of Trier et al. (2019) “Peptides, Antibodies, Peptide Antibodies and More”, International Journal of Molecular Sciences, 20, 6289, 22 pages (see PTO-892 06/24/2024).
Regarding claim 27, Di Guglielmo and the cited art above teaches a kit substantially as claimed.
Di Guglielmo is silent as to the minimum length of the region of proUGN that the antibody binds to.
Trier teaches that traditional peptide antibody production is based on immunization and that peptides used for immunization are usually 10-20 amino acids long (Trier, page 9, ‘4.2. Production’, lines 1-2). Trier further teaches that although peptides of 15-20 amino acids are often applied, an epitope is usually 5-8 amino acids long and therefore a peptide of 15-20 amino acids may give rise to an antibody response recognizing more than one epitope (Trier, page 9, 3rd paragraph, line 9-page 10, line 2).
It would have been prima facie obvious to one having ordinary skill before the effective filing date of the claimed invention, that the antibody be an antibody that binds to a region of at least 4 amino acids of full-length human proUGN, an N-terminal fragment of human proUGN, or a C-terminal fragment of human proUGN, because of the teaching of Trier that peptide epitopes for antibodies are usually 5-8 amino acids long. As such, it would have been prima facie obvious to one having ordinary skill that the antibody binds to a region of at least this length.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Di Guglielmo (as evidenced by BioVendor), in view of Goy, Payne, and Trier as applied to claim 27 above, and further in view of Miyazato et al. Cloning and characterization of a cDNA encoding a precursor for human uroguanylin. Biochemical and biophysical research communications. 1996 Feb 15;219(2):644-8.
Regarding claim 28, Di Guglielmo as evidenced by BioVendor and in view of the cited art above, teach a kit substantially as claimed, namely is teaching a kit comprising an antibody that binds human proUGN, or a fragment of post-translational modification thereof, wherein the human proUGN, or the fragment of post-translational modification thereof, is secreted from a human kidney cell.
Di Guglielmo does not teach that the antibody of claim 27 binds region of at least 4 amino acids of full-length human proUGN, which has the sequence set forth in SEQ ID NO: 1, the N-terminal fragment set forth in SEQ ID NO: 2, and the C-terminal fragments in SEQ ID NO: 3 and 4.
Miyazato teaches that SEQ ID No 1 recites the full length human proUGN, SEQ ID NO: 2 recites an N-terminal fragment, and SEQ ID NO: 3 and 4 recite C-terminal fragments. The limitations of the “wherein” clause recited at claim 28 fail to require any additional reagent or component be provided as part of the kit (for example the peptides are not claimed as part of the kit), and fails to impart any particular structural feature or limitation.
As such, it would be obvious that the monoclonal antibodies of Di Guglielmo in view of Goy would detect peptides comprised in SEQ ID No 1, because SEQ ID No 1 comprises the full-length sequence of human proUGN and since the monoclonal antibody of the combined prior art recognizes a peptide of human proUGN, the monoclonal antibody or the prior art is specific for a peptide comprised in SEQ ID No. 1.
Claim 29 are rejected under 35 U.S.C. 103 as being unpatentable over Di Guglielmo (as evidenced by BioVendor), in view of Goy, Payne, Trier and Miyazato, as applied to claim 28 above and further in view of Hidaka et al. (2000) “Dual Function of the Propeptide of Prouroguanylin in the Folding of the Mature Peptide”, The Journal of Biological Chemistry, 33, 18, pages 25155-25162 and Choi et al. (04/10/2006) “Fine epitope mapping of monoclonal antibodies specific to human α-synuclein” Neuroscience letters, 397, 1-2, pages: 53-58 (see PTO-892 06/24/2024).
Regarding claim 29, Di Guglielmo and the cited art above as applied to claim 28 teaches a kit for diagnosing chronic kidney disease, comprising a solid phase support and a first and second antibody wherein at least one of the first and second antibodies are monoclonal antibodies which specifically bind to human proUGN, substantially as claimed.
Di Guglielmo fails to teach that at least one of the antibodies binds to the N-terminal fragment of human proUGN as described in SEQ ID No: 2.
Hidaka teaches that the amino acid sequences of amino acid residues 1-23 and amino acid residues 38-65 of pre-prouroguanylin (pro-GCAP-II or SEQ ID No. 1) are highly homologous in all species, whereas amino acids 24-37 (N-terminal fragment) are diverse between different species (Hidaka, page 25157, 2nd paragraph, lines 6-10).
Choi teaches generating monoclonal antibodies against human α-synuclein (Choi, page 54, 2nd paragraph, lines 1-2). Choi further teaches that the human protein specific monoclonal antibody can be used as a valuable reagent for characterizing mice or zebrafishes transgenic for human protein (Choi, page 57, lines 1-3).
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 kit of di Guglielmo and the cited prior art, with an antibody raised against the N-terminal end of human proUGN. The artisan would have been motivated to target the N-terminal region, because of the teaching of Hidaka that amino acids 24-37 is highly diverse in different species. Thus, it would have been expected that the human protein would have a unique sequence in this region, and as such, an antibody raised against this region would have been expected to be specific for human proUGN. The artisan would have been motivated to generate a monoclonal antibody because of the teaching of Choi that monoclonal antibodies specific only for the human protein (such as those raised against the N-terminal region of human proUGN), can be used as a valuable reagent for characterizing transgenic animals expressing human protein (Choi, see page 57, lines 1-3). As such, a human specific antibody would have been expected to be capable of determining the presence/amount of transgenic protein, as opposed to native protein produced by the animal naturally. Therefore, it would have been obvious to generate a monoclonal antibody specific for human proUGN having an epitope within residues 24-37.
Once in possession of such a monoclonal antibody, it would have been obvious to include it in the ELISA kit of Di Guglielmo in place of Di Guglielmo’s proUGN antibody(ies) for use in, e.g., methods of measuring human protein produced from transgenic animals as suggested by Choi. As stated in MPEP §2144.06, substituting one equivalent element for another known for the same purpose renders an invention obvious and an “express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982)." One of ordinary skill in the art would have a reasonable expectation of success, because of the Di Guglielmo teaches ELISA kits comprising antibodies specific to human proUGN and Hidaka teaches an amino acid sequence in the human proUGN gene.
Claims 34 and 35 is rejected under 35 U.S.C. 103 as being unpatentable over Di Guglielmo, as evidenced by BioVendor, Goy and Payne as applied to claims 18 and 34 above, and further in view of Ariza et al. (2015) Analysis of a Urinary Biomarker Panel for Clinical Outcomes Assessment in Cirrhosis. PLOS ONE, 10, 14 pages (see PTO-892 06/24/2024).
Regarding claim 35, Di Guglielmo and the cited art above as applied to claim 18 teaches a kit substantially as claimed.
Di Guglielmo teaches a kit comprising additional biomarkers for measuring biomarkers in urine. Di Guglielmo fails to teach a kit for measuring creatinine.
Ariza teaches a kit for measuring various biomarkers for kidney disease, comprising antibodies bound to a substrate specific for calbindin, clusterin, IL-18, Kim-1 and MCP-1 and others, and biotinylated detection antibodies. Ariza further teaches that the urinary biomarkers were indexed to urinary creatinine to adjust for variability in urine concentration (Ariza, page 4, see ‘Measurement of urinary biomarkers’).
It would have been prima facie obvious to one having ordinary skill before the effective filing date of the claimed invention, to have modified the kit as taught by Di Guglielmo to add creatinine as a second biomarker, because creatinine levels can be used to adjust for variability in urine concentration.
One having ordinary skill in the art would have had a reasonable expectation of success in adding a second set of antibodies, specific for a second biomarker such as creatine, because Di Guglielmo teaches their kits as able to be applied for detecting multiple biomarkers.
Response to Arguments
Applicant's arguments filed 08/08/2025 have been fully considered but they are not persuasive.
Applicant argues regarding the rejection under 35 U.S.C. 112(a) starting on page 9, that the genus of antibody is not only described by its functional activity but by its sequence (derived from human proUGN) and that therefore there is a reasonable structure-function correlation between the structure of the invention and its function and that the first and second antibodies recited are antibodies derived from human proUGN, which has a specific sequence/structure.
This argument is not persuasive.
The antibody (the invention) is described by its specificity (specific from human proUGN). SEQ ID NO:1 describes the sequence of proUGN, not the sequence of the antibody. As explained previously in detail above, one of ordinary skill in the art cannot deduce the sequence or structure of the antibody from the sequence of the antigen it is specific for. See Harlow above teaches how the steps of the humoral immune response are well known in the art to be highly unpredictable. As such one of ordinary skill in the art could not readily predict the structure of the antibody from the antigen it binds to, even though the sequence of the antigen is known, and therefore there cannot be a reasonable structure-function correlation of the antibody as claimed.
The amendment including the sequence of human proUGN (SEQ ID NOs: 1-4) does not further define the sequence of the antibody as claimed but rather, as explained previously above, defines the sequence of the antigen.
Applicant further argues that it is known in the art that antibodies derived from a certain sequence will have a sequence complementary to a portion of the sequence it is derived from and that the recitation “derived from human proUGN” discloses sufficient structural features so that one of skill in the art can visualize or recognize members of the genus.
This argument is not persuasive.
Applicant does not provide evidence that antibodies have a sequence complementary to a portion of the sequence it is specific for, and further it is not readily clear what is meant, or what structure is implied by the language “complementary to”. As explained previously in detail above, it is unpredictable which antigenic determinant the antibody is specific for and what the structure of the antibody is, based on the protein sequence of the antigen (see Harlow and the cited art above).
Applicant further argues regarding the rejection under 35 U.S.C. 112(b) (starting at the bottom of page 9) that the phrase “derived from” in regards to the claimed antibody is not unclear. Applicant argues that antibody refers to a peptide or polypeptide derived from, modeled after or substantially encoded by an immunoglobulin gene, capable of binding an antigen or epitope and that one of ordinary skill in the art would understand that immunoglobulin gene refers to a gene that codes for the variable regions of antibody proteins. Applicant further argues that antibody production is well known in the art and can include determining the antigen the antibody will be engineered to detect and bind to and injecting the antigen into a laboratory animal to stimulate the animal’s immune system to produce antibodies against the antigen. In other words, applicant argues, antibodies are derived from antigens and this language is common in the art. In other words, applicant argues that antibodies are derived from an immunoglobulin gene and the further recites that it is common language in the art that antibodies are derived from antigens and therefore claim 18 is not indefinite.
This argument is not persuasive.
It is maintained that the language is unclear and indefinite because it is unclear how an antibody can both be derived from an immunoglobulin gene and be derived from an antigen. The relationship between an antibody and its antigen is commonly referred to as the antibody being specific to an antigen or epitope, but an antibody derived from a specific antigen is not commonly used and the claim language is unclear and the claim is therefore indefinite as recited by applicant above.
Applicant further argues, starting on page 10 regarding the rejection over 35 U.S.C. 103, that the inventors discovered that antibodies derived from human proUGN secreted from a human kidney cell work better than those derived from other species to detect human proUGN.
This argument is not persuasive.
The present claims are directed to a kit comprising monoclonal antibodies specific for human proUGN and the combination of the prior art teaches a kit comprising monoclonal antibodies specific for human proUGN. Di Guglielmo teaches an antibody capable of binding human derived proUGN, as Di Guglielmo teaches polyclonal antibodies comprising a species of antibodies specific for human derived proUGN, the secondary reference (see Goy) is relied on to teach a monoclonal, rather than polyclonal anti-proUGN antibody which is specific for mammalian derived proUGN. As explained in detail previously above, Goy teaches a method for producing a monoclonal antibody and Goy further teaches that the antibodies detects pro-uroguanylin from tissue samples of rat small intestine. Even though the exemplary species as taught by Goy is rat, Goy also teaches that the monoclonal antibodies can be produced from the epitopes described (rat and human proUGN sequences) and that the immunogen of interest is a portion of the prouroguanylin peptide distinct from the amino acid sequence of UGn18 in rats and UGn16 in humans. Goy further teaches that the invention pertains to human patients and that measuring the plasma levels of endogenous pro-uroguanylin is of diagnostic value in evaluating the status of patients with diseases such as kidney disease. As such Goy teaches a method comprising monoclonal antibody specific for proUGN produced by a mammalian cell, such as a human kidney cell. Payne provides the motivation for one of ordinary skill in the art to include a monoclonal, rather than a polyclonal antibody in the kit.
Applicant further argues starting on page 11 that Di Guglielmo teaches polyclonal antibodies and fails to teach that the antigen that the antibodies are specific for is secreted by a human kidney cell. Applicant further argues that Goy teaches an immunoassay kit for detecting pro-UGN in a sample and determining the presence of kidney disease and Goy teaches two antibodies against two regions of rat proUGN and the antibodies can be monoclonal (although the antibodies prepared in Goy are polyclonal). Applicant submits Goy teaches antibodies raised against rat proUGN and does not teach or suggest monoclonal antibodies that specifically bind human proUGN secreted from a human kidney cell.
These arguments are not persuasive.
As explained previously in detail above, Di Guglielmo in view of Goy teaches monoclonal antibodies specific for mammalian derived proUGN. Even though the exemplary species in Goy is rat, Goy also teaches monoclonal antibodies against mammalian derived anti-proUGN antibodies. Regarding the argument that the antibodies prepared in Goy are polyclonal, Goy teaches monoclonal antibodies specific for human pro-UGN .
Applicant further argues starting on page 11 that the amended claim 18 comprises SEQ ID NOs: 1-4 and as such comprises the human proUGN sequence. Applicant further argues that antibodies specific for a certain sequence will a have a sequence complementary to a portion of the sequence it is specific for and thus the claimed antibodies include sequences complementary to human proUGN, while the antibodies in Goy include sequences complementary to rat proUGN. Applicant further argues that rat and human proUGN sequences are very different and that neither Goy nor any of the cited references teach or suggest the claimed limitation “wherein the first and second antibodies include one or more amino acid sequence complementary to one or more portions of SEQ ID NO:1, 2, 3, or 4”.
These arguments are not persuasive.
As explained previously in detail above, it is unclear what applicant’s attorney is referring to by “a sequence complementary to” a portion of the sequence it is specific for. Further, Goy teaches monoclonal antibodies specific for human pro-UGN (see above). Still further, the recited SEQ ID NOs do not further define the antibody, but rather the sequence of the antigen and one cannot deduce the amino acid sequence of an antibody from the amino acid sequence of the antigen or even the specific epitope (see Harlow).
Applicant further argues on page 12 that in Goy, the proUGN used to make antibodies was obtained from rat tissue and that human proUGN has modifications not present in other species. Applicant further argues that the use of human kidney cells allows for expression of pre-proUGN, so that the proUGN can be folded appropriately, secreted from the cell as if it were in a mammalian host, and post-translationally modified in a way that is reflective of the human cell expression of proUGN. Applicant argues that the same concept is present in rats and that it is well known that proteins in different species can undergo different post translational modifications and can vary significantly across species.
This argument is not persuasive.
As discussed previously in detail above, even though the exemplary species in Goy is rat, Goy also teaches a monoclonal anti-human proUGN antibody and teaches selecting antibodies specific for binding protein secreted by cells of the target species.
Applicant argues that neither Goy nor any of the cited references disclose deriving antibodies from the same sequence as claimed, i.e., human proUGN secreted from a human kidney cell, let alone the same sequence with the same post-translational modification secreted from the same organism and cell type.
This argument is not persuasive.
Applicant argues (on page 12 of the declaration) that the polyclonal antibodies of Di Guglielmo are raised against E.coli derived proUGN which comprises added c-myc or histidine tags and is therefore different from human kidney cell derived proUGN. As discussed previously in detail above, Goy teaches the production of an anti-mammalian proUGN antibody which is tested against proUGN from the small intestine, i.e. specific for a mammalian derived proUGN antigen. Even though Goy’s exemplary species is rat, Goy also describes a monoclonal antibody specific for human proUGN. Therefore, in the present case, the prior art is teaching antibodies that specifically bind to human proUGN derived from a mammalian cells which would also bind human proUGN derived from a human kidney cell so it reads on the claim.
Applicant further argues on page 13 that there is no reason to modify the references and no reason to modify the references to include the missing subject matter. Applicant argues that the mainstream thinking at the time of filing was that proteins expressed by other species (e.g. rat, E.coli, etc) were able to accurately represent and reflect precise measurements of the human form of proUGN, thus there would be no reason to modify the BioVendor kit in the first place.
This argument is not persuasive.
Goy and Payne provide motivation to modify the assay of Di Guglielmo because the method of Goy of producing and testing monoclonal antibody to proUGN eliminates antibody cross-reactivity with pro-uroguanylin cleavage products or other irrelevant proteins and because of the teaching of Payne that monoclonal antibodies have improved assay sensitivity and specificity and help eliminate cross-reactivity frequently encountered with polyclonal reagents.
Applicant further argues that it was not known at the time of fling that human kidney cells produce the form of proUGN reflective of the onset of chronic kidney disease and that most scientists would have argued that generating new antibodies to a human kidney cell-line produced proUGN was a waste of money and that there was no reason for the ordinary artisan to expect that building a new device using proUGN from human kidney cells would render more accurate results than using proUGN secreted from another species, especially since Goy allegedly reports these antibodies are of diagnostic value. Applicant argues that therefore one of ordinary skill in the art would not be motivated to modify the two rat proUGN derived antibodies of Goy to be derived from human proUGN.
This argument is not persuasive.
As discussed previously above, the motivation to modify the kid of Di Guglielmo comprising polyclonal antibodies with the monoclonal antibodies of Goy is derived from the teaching of Goy and Payne that monoclonal antibodies eliminate cross-reactivity and therefore result in increased sensitivity and specificity regardless of what the intended use of the assay is.
Applicant further argues beginning on page 13 that there is no reasonable expectation of success. Applicant argues that as shown in Dr. Carrithers’ Expert Declaration (12/18/2023) the results were not predictable. Applicant argues that the inventors were the first to discover that an E. coli -based antibody device, like BioVendor’s kit, grossly overestimates or misrepresents the actual concentration of proUGN and that antibodies generated against recombinant E.coli -expressed proUGN do not accurately detect the human form of proUGN. . Applicant argues that as stated in Dr. Carrithers’ Expert Declaration, antibodies in the BioVendor kit are not accurately detecting human kidney cell-produced proUGN. Applicant argues that BioVendor’s kit does not use antibodies that are derived from human proUGN and there was no evidence at the time of filing that would indicate that there would be such alarming differences between two different ELISA systems and their ability to measure different cell line expressed proUGN standards and that the same goes for antibodies derived from rat proUGN as described in Goy or antibodies derived from other species and as such an ordinary artisan would have no reasonable expectation that using antibodies derived from proUGN secreted specifically from a human kidney cell would much more accurately measure human proUGN in a biological sample.
This argument is not persuasive.
The claims are directed to a kit comprising monoclonal antibodies specific for human proUGN derived from a human kidney cell, not an antibody device. The combination of the cited art teaches a kit comprising monoclonal antibodies specific for human derived proUGN and as such it meets the limitation of the claims because it would be expected that the antibodies of the cited prior art are indistinct (capable of same intended function, i.e., bind kidney derived proUGN).
For all the reasons above the arguments are not persuasive.
Communication
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/STEFANIE J. KIRWIN/Examiner, Art Unit 1677
/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677