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
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) were submitted on 12/8/2023 and 3/30/2026, before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 1-3, 6-8, 10-11, and 15-16 are pending. Claims 1-3, 6-8, 10-11, and 15-16 are under examination.
Claim Interpretation
Claims 15 is directed to a device for performing the method of claim 1. MPEP 2111.02(II) states: “During examination, statements in the preamble reciting the purpose or intended use of the claimed invention must be evaluated to determine whether or not the recited purpose or intended use results in a structural difference (or, in the case of process claims, manipulative difference) between the claimed invention and the prior art. If so, the recitation serves to limit the claim.”
No structural limitations are found in the method recited by claim 1 and therefore for claim 15, the preamble is interpreted to not confer and structural limitations.
Claim Objections
Claim 1 is objected to because of the following informalities. In the phrase “…screening for for binders to Pro-Tachykinin A or fragments thereof of at least 5 amino acids…”, the word “for” is repeated. Appropriate correction is required.
Claims 2-3, 6-8, and 10-11 are objected to because of the following informalities. These claims all being with “A method according to…”. For consistency of antecedent basis, reciting “The method according to…” Appropriate correction is required.
Examiner Note - 35 USC § 101
Due to one of the steps of the method claimed in claim 1 reciting: “… screening for for binders to Pro-Tachykinin A or fragments thereof of at least 5 amino acids …”, Examiner has considered a rejection under U.S.C. 101.
However, upon examination of the full claim language, a rejection under U.S.C. 101 is not rendered.
In this case, the active step of the method is receiving a binder and a sample. Furthermore, the binder is an antibody generated by the challenging of mammalian splenocytes with a peptide-BSA conjugate. Therefore, this binder is not a natural product and the method of receiving such a binder is also not a product of nature or natural phenomenon.
Similarly, the antibodies in claims 15 and 16 are generated by introducing human tachykinin fragments into a non-human splenocytes and producing the resulting antibodies artificially.
The active step of the claim does not receive a product of nature, therefore rejection under U.S.C. 101 is not appropriate for the present Application.
Claim Rejections - 35 USC § 112
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 1-3, 6-8, 10-11, and 15-16 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 1, it is not clear as to the relationship between the sample and the binder. Does the sample have binders in it? What in the sample is doing the binding? Is the sample bound to Pro-Tachykinin A? Clarification is required.
Consequently, claim 1 is rejected.
Regarding claims 2-3, 6-8, 10-11, and 15-16, claim 1 is rejected as described above. None of these claims correct the indefiniteness of claim 1, and therefore these claims are also rejected.
Claims 2-3, 6-8, 10-11, and 15-16 are rejected.
Regarding claim 8, claim 1 is rejected as described above. Claim 8 further recites the case wherein the level of bound Pro-Tachykinin A is measured with an immunoassay and said binder is an antibody, or an antibody fragment binding to Pro-Tachykinin A or fragments thereof of at least 5 amino acids.
It is not clear whether this refers to the Pro-Tachykinin A in the sample or the process for screening for binders or both. Clarification is required.
Claim 8 is rejected.
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, 6-8, and 10-11 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.
Regarding claim 1, claim 1 recites: “A method for comprising receiving a sample comprising bodily fluid from a subject that has not been diagnosed with sepsis or septic shock and a binder obtained by a process comprising: fusing splenocytes from a mammal previously immunized with a peptide-BSA-conjugate with cells of a myeloma cell line, and screening for for binders to Pro-Tachykinin A or fragments thereof of at least 5 amino acids; and wherein the sample has at least 75 pmol/L of bound Pro-Tachykinin A or fragments thereof of at least 5 amino acids.”
This method includes a two different genera of interest. The peptide-BSA-conjugate, as claimed, includes any possible peptide conjugated to BSA. Also the myeloma cell line, as claimed, includes any possible myeloma cell line.
In this case, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. (MPEP § 2163 (II.A.3.a.ii.))
According to MPEP § 2163 (II.A.3.a.ii.), a "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
As described above, claim 1 recites a huge sequence space of peptides and wide range of myeloma cell lines.
MPEP § 2163 (II.A.3.a.ii.) states that “for inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’”
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus.
Applicant discloses two peptides introduced into mammalian splenocytes and a single myeloma cell line.
Regarding the peptides, at the time the invention was made, the level of skill for preparing peptides with desired functional properties was high. However, even if a synthesis and selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify peptides that yield polypeptides with the recited properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure (length) provided by the provided species, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what peptide with a particular set of properties would look like structurally.
Applicant discloses two peptides for immunization.
Since only a limited number of species of peptides are taught within the claimed genus above, the instant claim above fails the written description requirement. A representative number of species has not been taught to describe this genus.
Regarding the peptides, a single point mutation can change the biophysical properties of a peptide: “In summary, we have shown that the structural changes in the fibrillar state of the Aβ42 peptide that are observed to occur upon introduction of single point mutations can be accompanied by changes in the dominance of the microscopic processes by which these aggregates are themselves formed.” (Bolognesi et al. ACS Chem Bio 9:2 (2013) page 381 col. 2 para. 3) and “In summary, while ovispirin-1 and novispirin G-10 both had solution structures that were helical and amphipathic in the presence of TFE, a relatively simple change in their primary structure (a single glycine–isoleucine exchange) had profound effects on their respective toxicities for human erythrocytes and epithelial cells.” (Sawai et al. Protein Eng. 15:3 (2002) page 232 col. 1 para. 3).
Furthermore, many sequences allowed by the current scope of the claims, result in non-functional aggregates. Wang (Wang, et al. MAbs. Vol. 1. No. 3. Taylor & Francis, (2009)) discloses a variety of aggregation prone motifs that occur in commercial antibodies (Wang, page 262, Table 2). The scope of the claims currently may incorporate such motifs and result in non-functional aggregates.
Finally, Zhou et al. (Zhou, et al. Biochimica et Biophysica Acta (BBA)-Biomembranes 1858.8: 1914-1925 (2016)) discloses that peptides are also subject to significant activity changes from a single mutation: “In our study, we constructed two anticancer peptides with only one difference in residue, but they showed dissimilar modes of action. One could penetrate into cells, target on mitochondria, and induce cell apoptosis, while the other could cause cell membrane lysis. This finding provides us a good example to study the structure-function relationship of ACPs as important drugs.” (Zhou et al., Abstract).
Given this unpredictability of protein design, the skilled artisan would not have been in possession of the substantial repertoire of peptide species encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of every peptide molecule recited by claim 1.
Regarding the myeloma cell lines, Köhler et al. (Köhler, et al. European journal of immunology 6.7: 511-519 (1976)) discloses that while Myeloma cell lines all possess the ability to stably express immunoglobulin proteins, not all cell lines are appropriate for production because they lose expression of the protein interest. This problem had to be engineered around:
“Antibody-producing cells normally express a single set of heavy (H) and light (L) chains. The expression of a single immunoglobulin (Ig) is a stable property of myeloma cells, and because such cells car? be grown in vitro, tissue culture techniques can be applied to the study and modification of this expression. The derivation of cell lines resulting from fusion of t w o Ig-producing cells [ 1 , 21 demonstrated that hybrids express all parental chains. The intracellular presence of both parental sets of L and H-chains resulted in the formation of new Ig, due to the heterologous association of chains from both parental origins. The specific anti-SRBC (sheep red blood cells) antibody production capacity of normal plasma cells was similarly preserved after fusion with myeloma cells, allowing the transfer of antibody specificity into a permanently growing new cell line [2]. Such hybrid cells expressed multiple Ig chains, which included the parental myeloma chains.
In hybrid lines, the loss of expression of specific chains is a frequently occurring event. Clonal screening procedures can therefore be used to derive sublines expressing different combinations of chains and consequently to establish the role of the different chains in the specific antibody activity. By this procedure we have succeeded in deriving sublines which only express the antibody-specific L and H-chain combination.” (Kohler, et al., page 511, col. 1, para. 1).”
Applicant discloses a single cell line: SP2/0, which is a known workhorse in the antibody production sector as disclosed by Geisse et al. (Geisse, et al. Protein expression and purification 8.3 : 271-282 (1996)): “Myeloma cells have been extensively used as fusion partners for the generation of antigen-specific hybridoma cell lines. As they are ‘‘professional’’ secretory cells, they are also well-suited for expression of recombinant genes introduced via transfection (11). In addition, because of their natural growth in suspension, a time-consuming adaptation to suspension culture for large scale production becomes superfluous. The mouse myeloma cell line Sp2/0 Ag14, which is incapable of synthesizing or secreting endogenous immunoglobulins (43) represents one choice of a myeloma cell line for recombinant protein production. (Geisse et al., page 273, col. 1, para. 2).
Since only a limited number of species of cell lines are taught within the claimed genus above, the instant claim above fails the written description requirement. A representative number of species has not been taught to describe this genus. Almost assuredly, other cell lines exist in the art that are capable of being exchanged for SP2/0, but as Köhler describes above, not all Myeloma cells are suitable for antibody production.
The skilled artisan would not have been in possession of the substantial repertoire of cell line species encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of every cell line recited by claim 1.
Consequently, claim 1 is rejected.
Regarding claims 2-3, 6-8, and 10-11 claim 1 is rejected as described above. None of these claims reduce the size of the genera discussed above for claim 1.
Consequently, claims 2-3, 6-8, and 10-11 are rejected.
Claims 1-3, 6-8, and 10-11 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the method of claim 1 wherein the bodily fluid is serum, plasma, or blood and also wherein splenocytes from a mouse previously immunized with a peptide-BSA-conjugate wherein the peptide is SEQ ID NO: 11 or SEQ ID NO:12 are fused with cells of the SP2/0 line, is not enabling for the case wherein the bodily fluid is any possible bodily fluid and wherein splenocytes from any possible mammal previously immunized with any possible peptide-BSA-conjugate are fused with cells of any possible myeloma line. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024). These factors include, but are not limited to:
The breadth of the claims;
These claims are broad because they encompass any possible bodily fluid, any possible mammalian splenocyte, with any possible peptide-BSA conjugate, and any possible myeloma cell line.
The nature of the invention;
The invention is a method for comprising receiving a sample comprising bodily fluid from a subject that has not been diagnosed with sepsis or septic shock and a binder obtained by a process comprising: fusing splenocytes from a mammal previously immunized with a peptide-BSA-conjugate with cells of a myeloma cell line, and screening for binders to Pro-Tachykinin A or fragments thereof of at least 5 amino acids; and wherein the sample has at least 75 pmol/L of bound Pro-Tachykinin A or fragments thereof of at least 5 amino acids
This method is partially describing a process of generating antibodies that are capable of binding to Pro-Tachykinin A or fragments thereof.
The state of the prior art;
This analysis, similar to the written description rejection above, uses different veins of prior art.
Regarding the bodily fluid, different bodily fluids have different compositions as disclosed by Hu et al. (Hu, et al. Proteomics 6.23: 6326-6353. (2006)): ” There is a minimum overlapping of proteins identified from different body fluids, suggesting that the proteomic content in each body fluid is distinct. This also implies that the analytical methods need to be optimized for a specific body fluid proteome, and there is no such universal proteomics platform for all the body fluids.” (Hu et al, page 6343, col. 2, para. 4).
Regarding the peptide, the issue is predictability of the broad range of claimed peptides providing appropriate outcomes in the immunization step.
A single point mutation can change the biophysical properties of a peptide: “In summary, we have shown that the structural changes in the fibrillar state of the Aβ42 peptide that are observed to occur upon introduction of single point mutations can be accompanied by changes in the dominance of the microscopic processes by which these aggregates are themselves formed.” (Bolognesi et al. ACS Chem Bio 9:2 (2013) page 381 col. 2 para. 3) and “In summary, while ovispirin-1 and novispirin G-10 both had solution structures that were helical and amphipathic in the presence of TFE, a relatively simple change in their primary structure (a single glycine–isoleucine exchange) had profound effects on their respective toxicities for human erythrocytes and epithelial cells.” (Sawai et al. Protein Eng. 15:3 (2002) page 232 col. 1 para. 3).
Furthermore, many sequences allowed by the current scope of the claims, result in non-functional aggregates. Wang (Wang, et al. MAbs. Vol. 1. No. 3. Taylor & Francis, (2009)) discloses a variety of aggregation prone motifs that occur in commercial antibodies (Wang, page 262, Table 2). The scope of the claims currently may incorporate such motifs and result in non-functional aggregates.
Finally, Zhou et al. (Zhou, et al. Biochimica et Biophysica Acta (BBA)-Biomembranes 1858.8: 1914-1925 (2016)) discloses that peptides are also subject to significant activity changes from a single mutation: “In our study, we constructed two anticancer peptides with only one difference in residue, but they showed dissimilar modes of action. One could penetrate into cells, target on mitochondria, and induce cell apoptosis, while the other could cause cell membrane lysis. This finding provides us a good example to study the structure-function relationship of ACPs as important drugs.” (Zhou et al., Abstract).
Taken together, it is too unpredictable that any possible peptide will provide the outcome needed to make the method as a whole work correctly.
Regarding the cell line, Köhler et al. (Köhler, et al. European journal of immunology 6.7: 511-519 (1976)) discloses that while Myeloma cell lines all possess the ability to stably express immunoglobulin proteins, not all cell lines are appropriate for production because they lose expression of the protein interest. This problem had to be engineered around:
“Antibody-producing cells normally express a single set of heavy (H) and light (L) chains. The expression of a single immunoglobulin (Ig) is a stable property of myeloma cells, and because such cells car? be grown in vitro, tissue culture techniques can be applied to the study and modification of this expression. The derivation of cell lines resulting from fusion of two Ig-producing cells [ 1 , 21 demonstrated that hybrids express all parental chains. The intracellular presence of both parental sets of L and H-chains resulted in the formation of new Ig, due to the heterologous association of chains from both parental origins. The specific anti-SRBC (sheep red blood cells) antibody production capacity of normal plasma cells was similarly preserved after fusion with myeloma cells, allowing the transfer of antibody specificity into a permanently growing new cell line [2]. Such hybrid cells expressed multiple Ig chains, which included the parental myeloma chains.
In hybrid lines, the loss of expression of specific chains is a frequently occurring event. Clonal screening procedures can therefore be used to derive sublines expressing different combinations of chains and consequently to establish the role of the different chains in the specific antibody activity. By this procedure we have succeeded in deriving sublines which only express the antibody-specific L and H-chain combination.” (Kohler, et al., page 511, col. 1, para. 1).”
Applicant discloses a single cell line: SP2/0, which is a known workhorse in the antibody production sector as disclosed by Geisse et al. (Geisse, et al. Protein expression and purification 8.3 : 271-282 (1996)): “Myeloma cells have been extensively used as fusion partners for the generation of antigen-specific hybridoma cell lines. As they are ‘‘professional’’ secretory cells, they are also well-suited for expression of recombinant genes introduced via transfection (11). In addition, because of their natural growth in suspension, a time-consuming adaptation to suspension culture for large scale production becomes superfluous. The mouse myeloma cell line Sp2/0 Ag14, which is incapable of synthesizing or secreting endogenous immunoglobulins (43) represents one choice of a myeloma cell line for recombinant protein production. (Geisse et al., page 273, col. 1, para. 2).
(D) The level of one of ordinary skill;
A person of ordinary skill in the art in the field of antibody production and binder screening is usually at least a Master’s level education.
(E) The level of predictability in the art;
As described above, the predictability of this art is very poor for peptides and cell lines are only predictable after their phenotypic properties are established and documented.
(F) The amount of direction provided by the inventor and the existence of working examples and the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Regarding claim 1, there are different aspects to examine.
First, the claimed genus of bodily fluids encompasses bodily fluids with different compositions and different proteomes as disclosed by Hu above. Because of this divergence in compositions, it would require undue experimentation for a person of ordinary skill in the art to test the efficacy of all possible bodily fluids in the claimed method.
Next, the claimed peptide genus is very broad and very few peptides are shown to provide the desired method outcome. Because the exact activity and immunization outcome of any given peptide is unpredictable as described above, it would require undue experimentation for a person of ordinary skill in the art to test the efficacy of all possible peptides in the claimed method.
Lastly, the myeloma cell line genus is far less broad, but still contains many members that are not appropriate for antibody production as outlined by Köhler. Due to varying levels of loss of expression of protein of interest, it would require undue experimentation to determine out of all possible myeloma cell lines which ones will provide sufficient amounts and purity of the desired antibody.
Consequently, claim 1 is rejected.
Regarding claims 2-3, 6-8, and 10, these claims do not reduce the genus size of the peptide or the myeloma cell line.
Consequently, claims 2-3, 6-8, and 10 are rejected.
Regarding claim 11, claim 1 is rejected as described above. Claim 11 reduces the genus size of bodily fluids to blood, serum, plasma, urine, cerebrospinal fluid (CSF), and saliva. Hu shows that urine, CSF, and saliva have significantly different proteomes than blood, serum, and plasma in Table 1 (Hu et al., page 6329, Table 1). Because of this divergence in compositions, it would require undue experimentation for a person of ordinary skill in the art to test the efficacy of all possible bodily fluids in the claimed method.
Consequently, claim 11 is rejected.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 15 and 16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bergmann et al. US 2020/0182885, published 6/11/2020.
Regarding claim 15, claim 15 recites a point-of-care device for performing a method according to claim 1, wherein said point of care device comprises at least two antibodies or antibody fragments directed to amino acid 3-22 (SEQ ID NO. 11) and amino acid 21- 36 (SEQ ID NO. 12).
Because the preamble has been interpreted as not limiting the structure of the claimed device, claim 15 of US 2020/0182885: “A point-of-care device for performing a method according to claim 1, wherein said point of care device comprises at least two antibodies or antibody fragments directed to amino acid 3-22 (SEQ ID NO. 11) and amino acid 21-36 (SEQ ID NO. 12).”
These amino acids are identical to SEQ ID NO: 11 and 12 of the present application: “In one embodiment subject matter of the present invention is a point-of-care device for performing a method according to the invention wherein said point of care device comprises at least one antibody or antibody fragment directed to either amino acid 3-22 (GANDDLNYWSDWYDSDQIK, SEQ ID NO. 11) or amino acid 21-36 (IKEELPEPFEHLLQRI, SEQ ID NO. 12) wherein each of said regions comprises at least 4 or 5 amino acids.” (Bergmann et al., para. [0166].)
Consequently, claim 15 is anticipated by Bergmann et al. and rejected.
Regarding claim 16, claim 16 recites a kit for performing a method according to claim 1, wherein said kit comprises at least two antibodies or antibody fragments directed to amino acid 3-22 (SEQ ID NO. 11) and amino acid 21-36 (SEQ ID NO.12).
Because the preamble has been interpreted as not limiting the structure of the claimed device, claim 16 of US 2020/0182885: “A kit for performing a method according to claim 1, wherein said kit comprises at least two antibodies or antibody fragments directed to amino acid 3-22 (SEQ ID NO. 11) and amino acid 21-36 (SEQ ID NO.12).”
These amino acids are identical to SEQ ID NO: 11 and 12 of the present application: “In one embodiment subject matter of the present invention is a point-of-care device for performing a method according to the invention wherein said point of care device comprises at least one antibody or antibody fragment directed to either amino acid 3-22 (GANDDLNYWSDWYDSDQIK, SEQ ID NO. 11) or amino acid 21-36 (IKEELPEPFEHLLQRI, SEQ ID NO. 12) wherein each of said regions comprises at least 4 or 5 amino acids.” (Bergmann et al., para. [0166].)
Consequently, claim 16 is anticipated by Bergmann et al. and rejected.
Free of the Prior Art
Claims 1-3, 6-8, and 10-11 are not allowable as described above, but they are free of prior art rejections.
The prior art discloses the concept of using bradykinins to anticipated sepsis, but does not disclose the recited method, nor supply sufficient motivation or detail to render such a method obvious.
For example, Lindström et al. (Lindström, et al. Clinica Chimica Acta 493: 20-24. (2019)) discloses an LC-MS/MS method: “Previously, bradykinin-2 –receptor antagonist deltibant led to reduced mortality in human cases with pure gram-negative etiology [22] and severe hantavirus infection for septic shock suggesting bradykinin involvement in these conditions. However, we did not find higher bradykinin concentrations in our patients with proven or suspected gram-negative origin for septic shock (Table 1). Instead, we found that bradykinin concentration in samples from healthy individuals was higher than that in patient samples (p < 0.0001), although still in the low nanomolar range. Thus, determination of plasma bradykinin in septic shock patients cannot be suggested to support the definition of use of bradykinin-2 receptor antagonists.
In conclusion, our newly developed LC-MS/MS assay is well suited for research purposes. Although the majority of patient plasma bradykinin concentrations turned out too low to quantify accurately, healthy individual plasma concentrations were within the linear measurement range. The protease inhibitor mix preserved the samples when frozen for at least 12 months. The developed assay can potentially be utilized for studying other bradykinin mediated medical conditions in the future.” (Lindström et al., page 23, col. 2, para. 4).
Goh et al. (Goh, et al. Nature communications 12.1: 711. (2021)) discloses an AI based method for predicting sepsis: “Sepsis is a leading cause of death in hospitals. Early prediction and diagnosis of sepsis, which is critical in reducing mortality, is challenging as many of its signs and symptoms are similar to other less critical conditions. We develop an artificial intelligence algorithm, SERA algorithm, which uses both structured data and unstructured clinical notes to predict and diagnose sepsis. We test this algorithm with independent, clinical notes and achieve high predictive accuracy 12 hours before the onset of sepsis (AUC 0.94, sensitivity 0.87 and specificity 0.87). We compare the SERA algorithm against physician predictions and show the algorithm’s potential to increase the early detection of sepsis by up to 32% and reduce false positives by up to 17%. Mining unstructured clinical notes is shown to improve the algorithm’s accuracy compared to using only clinical measures for early warning 12 to 48 hours before the onset of sepsis.” (Goh et al., Abstract).
It is difficult to say which of these is the “closest” prior art, because none of them are employing antibody production to then screen for bradykinin and fragments thereof. They are close in the sense that they are methods that are seeking to achieve a similar goal. Regardless, the prior art does not supply sufficient teaching or motivation to render the claimed method obvious.
Conclusion
Claims 1-3, 6-8, and 10-11 are objected to.
No claimed is allowed.
Claims 1-3, 6-8, 10-11, and 15-16 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to David Paul Bowles whose telephone number is (571)272-0919. The examiner can normally be reached Monday-Friday 8:30-5:00.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654
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