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 .
Election/Restrictions
Applicant’s election without traverse of Group IV (claims 14-17) in the reply filed on 05/18/2026 is acknowledged. It is noted that because Applicant did not distinctly and specifically point out any errors in the restriction requirement, the election has been treated as an election without traverse (MPEP 818.03(a)).
Claim Status
Claims 4-9, 12-13, and 16-17 have been amended as requested in the preliminary amendment filed on 10/06/2023. Following the amendment, claims 1-20 are pending in the instant application.
Claims 1-13 and 18-20 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions in the Response filed 05/18/2026, there being no allowable generic or linking claim.
Claims 14-17 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 14-17 have an effective filing date of October 7, 2022 corresponding to PRO 63/378,840.
Specification
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The abstract of the disclosure is objected to because it is less than 50 words in length. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is further objected to because it contains an embedded hyperlink and/or other form of browser-executable code at Page 1. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is further objected to for the use of the term nanobodies (see Page 12), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 16-17 are objected to because of the following informalities: the claims utilize inconsistent references to steroid-phosphoethanolamine diesters (designated by structure identifiers starting with “E”) and phosphocholine diesters (designated by structure identifiers starting with “C”). For example, claim 16 identifies the steroid-phosphoethanolamine as "E381", and specifies that the antibodies are selected for "steroid C381". Claim 17 recites various structures corresponding to "the diester" (i.e., the steroid-phosphoethanolamine), wherein the structures thereof are labeled as "steroid E313", "steroid E329", "steroid E341", "steroid E353", "steroid E369", "steroid E371", and "steroid E381" and recites that the antibodies are selected for the "corresponding steroid phosphocholine diester". Applicant should amend the claims such the reference to steroid-phosphoethanolamine diesters and the corresponding phosphocholine diesters are consistent across all of the claims. Appropriate correction is required.
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.
Claims 14-15 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. This is a WRITTEN DESCRIPTION rejection.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. To satisfy the written description requirement, a patent 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. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
The claims are drawn to a genus of steroid-phosphoethanolamine diesters and, subsequently, said diesters as haptens (see claim 14). It is specifically noted that Page 1 of the specification indicates that the steroids encompassed by the invention are spiral steroids, which (i) may have 23, 24 or 25 carbon atoms, (ii) are phosphodiesters, and (iii) contain a spiral steroid at carbon # 17, or are a precursor thereof. The chemical structures of 13 steroid compounds (6 phosphocholine diesters and 7 phosphoethanolamine diesters) are provided at Pages 7-10 of the specification, and are adequately described. A hapten is known in the art to be a molecule that on its own is incapable of eliciting an immune response. Applicant does not specifically define “hapten”, and on Page 19 the specification indicates that the steroid compounds described herein are relatively small molecules, and that conjugating the targeted steroid compound to a carrier protein (resulting in a hapten) may be done for improved success; for example, because E381 has an amine group that can facilitate a coupling reaction, E381 may be a particularly good candidate for conjugating to a carrier protein (i.e. a hapten). However, even though Applicant has disclosed numerous species of steroid-phosphoethanolamine diesters, Applicant is claiming any steroid-phosphoethanolamine diester, which encompasses a large and structurally diverse genus of steroid-phosphoethanolamine diester species which, absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed. Accordingly, Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genus, and Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
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 applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; and see Enzo Biochem, Inc. V. Gen-Probe Inc.
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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. As previously indicated, Applicant has disclosed numerous species within the genus claimed. However, given the large number of species encompassed by the genus claimed as well as the high level of structure variation that would be displayed by members of the claimed genus, the disclosure of said numerous adequately described species is not sufficiently representative of the entire genus.
Accordingly given the large number of species encompassed by the genus claimed as well as the high level of structure variation that would be displayed by members of the claimed genus and given the lack of particularity with which the claimed any steroid-phosphoethanolamine diesters are described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the instant disclosure fails to demonstrate that Applicant was in possession of the claimed invention at the time the application was filed.
Claims 14 and 16-17 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is an ENABLEMENT rejection.
The Breadth of the Claims
Independent claim 14 is drawn to a method of producing monoclonal and/or polyclonal antibodies comprising (i) isolating specific steroid-phosphoethanolamine diesters and (ii) preparing monoclonal and/or polyclonal antibodies using said diesters as a hapten. Under the broadest reasonable interpretation, and absent any special definitions, the method of claim 14 is drawn to producing monoclonal and/or polyclonal antibodies comprising isolating (i) any steroid-phosphoethanolamine diester and (ii) using the diesters as a hapten, wherein a hapten itself as known in the art does not elicit an immune response. As such, as currently presented the method of claim 14 is not enabled as the diesters on their own (i.e., as unconjugated haptens) are incapable of eliciting an immune response and therefore cannot be used on their own to produce antibodies.
The State of the Prior Art/Level of Unpredictability in the Art
Bauminger et. al. (Journal of Steroid Biochemistry, 1974, 5, 739-747) teach that by judicious choice of the site of attachment of steroid haptens to a protein carrier it is possible to elicit the formation of antibodies with enhanced specificity towards selected parts of the steroid molecule; coupling the steroid through a position remote from the functional groups responsible for its hormonal specificity preserves these substituents as antigenic determinants (Abstract). Bauminger et. al. cite pioneering work of Lieberman and colleagues, which established that steroid hormones can function as antigenic determinants when covalently linked to a protein carrier; in the design of such antigenic conjugates, several variables have to be considered including (i) the site on the steroid molecule through which the link is effected, (ii) the chemical nature and length of the bridge connecting hapten and carrier, (iii) the nature of the carrier chosen, and (iv) the number of steroid residues attached to each carrier molecule (Page 739, Column 1, First Paragraph). Bauminger et. al. disclose methods for attaching steroids to a protein carrier in such a way that the characteristic functional groups of the hormone or metabolite are preserved as antigenic determinants; sera obtained by use of antigens conjugated through positions 1, 6, 7 or 11, it proved possible to develop radioimmunoassay procedures for the direct determination of the primary gonadal hormones (testosterone, progesterone and oestradiol) in un fractionated lipid extracts of plasma in a number of defined physiological conditions, and in culture media, with reasonable accuracy, and by a similar approach, antisera have now been developed that will preferentially bind important metabolites of gonadal steroids, such as oestrone and oestriol, androstenedione and 5α-dihydrotestosterone, 17-hydroxyprogesterone and 20α-dihydroprogesterone.
Tian et. al. (Chem. Biol. Technol. Agric., 2018, 5(5), 1-12) teaches that environmental hormones, also called environmental endocrine-disrupting chemicals (EDCs), are mainly produced by various human activities and environment pollution; these hormones have similar structures to natural hormones, and they can easily interfere with the normal hormone function of human body (Page 1, Column 1, First Paragraph). Tian et. al. review current immunoassays applicable for the determination of trace environmental hormones (estrogens, progestagens, testosterone, etc.) with the emphasis on the preparation of antigen and production of antibody (Page 3, Column 1, Second Full Paragraph). Tian et. al. specifically indicate that most of hormones are small molecular compounds which are called haptens (molecular weight less than 1000), they will not be able to stimulate the animals to produce specific antibodies directly; however, the hapten can be modified to introduce an accessible functional group as well as a connecting arm and then combined with macromolecular carrier wherein this hapten–carrier conjugate can be regarded as the artificial antigen, possessing immunogenicity (Page 3, Last Paragraph of Column 1 through First Partial Paragraph of Column 2). If there are any active groups in the hapten molecule, such as –COOH, –NH, –OH, they will be coupled with carrier directly; if not, the hapten should be redesigned, wherein previous work proposed the design principles of hapten molecules and expressed the common apprehension in producing antibodies with respect to low-molecular compounds (Page 3, Column 2, First Full Paragraph). Figure 3 of Tian et. al. (reproduced below) depicts the processes of antigen and antibody production:
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Thus, the art establishes that steroids on their own are not sufficient for use as antigens in the production of steroid-specific antibodies as on their own they do not generate an immune response. Rather, the steroids must be conjugated to a carrier protein/polypeptide to be useful in the production of antibodies (i.e., monoclonal or polyclonal antibodies) as conjugation of the steroid to a carrier protein/polypeptide is what enables the steroid to function as an antigen and generate an immune response.
The Amount of Direction Provided by the Inventor/Existence of Working Examples
It is specifically noted that Page 1 of the specification indicates that the steroids encompassed by the invention are spiral steroids, which (i) may have 23, 24 or 25 carbon atoms, (ii) are phosphodiesters, and (iii) contain a spiral steroid at carbon # 17, or are a precursor thereof. As detailed above, a hapten is known in the art to be a molecule that on its own is incapable of eliciting an immune response. Applicant does not specifically define “hapten”, and on Page 19 the specification indicates that the steroid compounds described herein are relatively small molecules, and that conjugating the targeted steroid compound to a carrier protein (resulting in a hapten) may be done for improved success; for example, because E381 has an amine group that can facilitate a coupling reaction, E381 may be a particularly good candidate for conjugating to a carrier protein (i.e. a hapten). Thus, the instant specification explicitly indicates that the steroid compounds of the invention must be conjugated to a polypeptide/carrier protein (i.e., to form an immunogenic composition) in order produce antibodies that are highly specific and highly sensitive for the steroid compounds. There are no working examples demonstrating that the steroids on their own (i.e., unconjugated haptens) are capable of eliciting an immune response to produce antibodies.
Examiner Suggestion: It is suggested that Applicant could amend independent claim 14 such that the scope of the method claim is narrowed to (i) isolating spiral steroid-phosphoethanolamine diesters (e.g., E313, E329, E353, E369, E371, and/or E381 as provided/supported by the instant specification and dependent claims 16-17) and (ii) preparing monoclonal and/or polyclonal antibodies by conjugating the spiral steroid-phosphoethanolamine diesters to a carrier protein/polypeptide to from an immunogenic composition (i.e., an antigen), immunizing an animal with said immunogenic composition, and collecting monoclonal and/or polyclonal antibodies from the animal (as provided in dependent claim 15).
Claim Interpretation
It is specifically noted that for the purposes of applying art, “specific steroid-phosphoethanolamine diester” as recited in claim 14 is being interpreted as spiral steroid-phosphoethanolamine diesters (e.g., E313, E329, E353, E369, E371, and/or E381). Additionally, it is noted that “using the diester as a hapten” in claim 14 is being interpreted as conjugating a carrier protein/polypeptide to a spiral steroid-phosphoethanolamine diester.
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.
Claims 14-17 are rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Chasalow et. al. (Non-Patent Literature Citation No. 4 on 10/06/2023 IDS; herein after referred to as "Chasalow") in view of non-patent literature by Chasalow (Preprints, Posted July 2020, 1-2; herein after referred to as "Chasalow-2") and non-patent literature by Tian et. al. (Chem. Biol. Technol. Agric., 2018, 5(5), 1-12; herein after referred to as "Tian").
Chasalow teaches that pre-eclampsia is a condition that complicates 3–6% of pregnancies, and at present, there is no FDA approved diagnostic method to evaluate risk or progression; the authors report their observation of elevated levels of the spiral steroid phosphoester precursor in patients with pre-eclampsia; of the samples from the women with pre-eclampsia, 12 of 19 (63%) samples had Z-scores over 2.0 for at least one of the steroid phosphoesters whereas, in contrast, current markers under development for risk of pre-eclampsia have prediction scores ranging from 8 to 33% (Abstract). The authors discovered a spiral steroid phosphocholine ester which may identify patients at risk of developing pre-eclampsia (see Fig. 1) wherein a spiral steroid has a bridge carbon that is part of two rings and the bridge is at carbon 17 and it is part of the D-ring of the steroid and is also part of the E-ring lactone; spiral steroids are unusual in that the E-ring is perpendicular to the general plane of the steroid (Page 1 Last Paragraph of Column 2 through Page 2 First Paragraph of Column 1; Figure 1). More specifically, Fig. 1 (reproduced below) shows the proposed structures of the new compounds that we detected by electrospray ionization (ESI) mass spectrometry (MS); it is specifically noted that
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phosphoesters are attached at carbon 3 (Page 2, Column 1, First Partial Paragraph):
Pregna-5,7-diene-3β,17α-diol-20-one (structure shown in Fig. 1, top left) is synthesized by side-chain cleavage of 7-dehydrocholesterol and subsequent 17a- hydroxylation; pregna-5,7-diene-3β,17α-diol-20-one is the substrate for addition of the phosphoethanolamine and, in turn, the phosphoester condenses with acyl CoA and two steps are needed to form the spiral structure: (i) formation of the cyclic lactone and loss of water to form the Carbon 20-Carbon 23 alkene, and (ii) the steroid is reduced in ring B and the amino group is tri-methylated (Page 4, Column 2, Second Full Paragraph through Last Paragraph). When the co-substrate (for pregna-5,7-diene-3β,17α-diol-20-one) is acetyl-CoA, the product is Ionotropin (Figure 1, bottom left); F381 is formed if the co-substrate is acetoacetyl-CoA (Page 5, Column 1, First Partial Paragraph). Thus, the phosphoester structure corresponding to pregna-5,7-diene-3β,17α-diol-20-one with the added phosphoethanolamine at carbon 3 is shown below:
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Chasalow specifically suggests that there may be a benefit to combine spiral steroid assay with other previously proposed biomarkers for pre-eclampsia; blood tests are already routinely drawn at 16 and 28 weeks of pregnancy and either time point might be a good opportunity to obtain blood samples to test potential markers for preeclampsia, and identification and application of a marker, like the spiral steroids and/or their precursor, C313, might provide a basis for monitoring disease progression and permit development of improved therapeutic modalities wherein the identification of patients needing a higher level of scrutiny during the remainder of pregnancy might result in reduced maternal/fetal morbidity and mortality (Page 5. Column 2, Second Full Paragraph).
However, Chasalow does not explicitly teach or suggest the phosphoester structure for F381, nor methods for producing antibodies specific to the disclosed spiral steroids, specifically comprising conjugating the steroids to a carrier protein/polypeptide. These deficiencies are remedied by Chasalow-2 and Tian.
Chasalow-2 discloses, in addition to the major steroid compounds in adrenals and ovaries of while the bulk of the reference describes, a few unexpected ions in the spectra from pregnant women; these ions are in the range characteristic of the steroid fragments and have solubility properties of phosphoesters but parent ions were not recognized under the conditions of analysis (Page 13, Section 2.1.10). When the authors recognized the role of acyl coenzyme A in the biosynthesis, they proposed structures that fit the pattern for the two major unexplained peaks as shown in Figure 10 (reproduced below; see Page 13).
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Thus, Chasalow-2 discloses the proposed parent phosphoester structure corresponding to F381 of the Chasalow reference above, wherein the parent phosphoester comprises phosphoethanolamine attached at carbon 3 (similar to the parent phosphoester of pregna-5,7-diene-3β,17α-diol-20-one).
Tian teaches that environmental hormones, also called environmental endocrine-disrupting chemicals (EDCs), are mainly produced by various human activities and environment pollution; these hormones have similar structures to natural hormones, and they can easily interfere with the normal hormone function of human body (Page 1, Column 1, First Paragraph). Tian et. al. review current immunoassays applicable for the determination of trace environmental hormones (estrogens, progestagens, testosterone, etc.) with the emphasis on the preparation of antigen and production of antibody (Page 3, Column 1, Second Full Paragraph). Tian specifically indicates that most of hormones are small molecular compounds which are called haptens (molecular weight less than 1000), they will not be able to stimulate the animals to produce specific antibodies directly; however, the hapten can be modified to introduce an accessible functional group as well as a connecting arm and then combined with macromolecular carrier wherein this hapten–carrier conjugate can be regarded as the artificial antigen, possessing immunogenicity (Page 3, Last Paragraph of Column 1 through First Partial Paragraph of Column 2). If there are any active groups in the hapten molecule, such as –COOH, –NH, –OH, they will be coupled with carrier directly; if not, the hapten should be redesigned, wherein previous work proposed the design principles of hapten molecules and expressed the common apprehension in producing antibodies with respect to low-molecular compounds (Page 3, Column 2, First Full Paragraph). Usually, the primary carrier proteins are bovine serum albumin (BSA), ovalbumin (OVA), keyhole hemocyanin (KLH), human serum albumin (HSA), and rabbit serum albumin (RSA), and it is possible to elicit antibodies with affinity to haptens by conjugating to such protein forming an immunogen; among these, BSA is the most popular one, due to its stability of physical and chemical properties, low price, easy obtainability, and highly successful rate of conjugation (Page 5, Column 1, First Full Paragraph). Tian further teaches that the key to establish an immunoassay for small molecular compounds and guarantee precise measurements is to produce antibody with high affinity and high selectivity, especially when the concentrations of compounds are at trace levels (Page 6, Column 2, First Full Paragraph). Figure 3 of Tian (reproduced below) depicts the processes of antigen and antibody production:
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Among the various rapid-detection techniques, immunoassay is the most widely used one because of its adaptability of different kinds of samples and its convenience of operation; highly sensitive detection of EDCs can be performed by the following assays: radioimmunoassay, enzyme-linked immunosorbent assay; chemiluminescence immunoassay, fluorescence immunoassay, lateral flow assay, as well as other methodologies based on antibody or combined with antibody such as immunosensor, molecularly imprinted technique, and surface plasma resonance sensing (see Pages 7-9). Thus, Tian discloses methods of producing antibodies (monoclonal and/or polyclonal antibodies) to small molecule haptens, including steroids as an example, wherein conjugation to a carrier protein allows for immune stimulation and antibody production against the hapten (i.e., steroid) and discloses the use of such antibodies for the detection of the hapten using immunoassays and related antibody-based methodologies.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, it is specifically noted that (i) Chasalow teaches newly identified spiral steroid compounds which may identify patients at risk of developing pre-eclampsia and suggests that there may be a benefit to combine spiral steroid assay with other previously proposed biomarkers for pre-eclampsia wherein identification and application of a marker, like the spiral steroids and/or their precursors, might provide a basis for monitoring disease progression and permit development of improved therapeutic modalities wherein the identification of patients needing a higher level of scrutiny during the remainder of pregnancy might result in reduced maternal/fetal morbidity and mortality; (ii) Chasalow-2 discloses the proposed parental phosphocholine structure (i.e., precursor structure) corresponding to the compound F381 initially disclosed by Chasalow; and (iii) Tian discloses methods of producing antibodies (monoclonal and/or polyclonal antibodies) to small molecule haptens, including steroids as an example, wherein conjugation to a carrier protein allows for immune stimulation and antibody production against the hapten (i.e., steroid) and discloses the use of such antibodies for the detection of the hapten using immunoassays and related antibody-based methodologies and thus making and using antibodies specific to steroid compounds is known and established in the art.
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to isolate, for example, the parental phosphoester structure of F381 of Chasalow, said parental phosphoester comprising phosphoethanolamine attached at carbon 3 as taught by Chasalow-2, and conjugate said parental phosphoester to a carrier protein/polypeptide to form an immunogenic composition to generate an antigen capable of eliciting an immune response in an animal upon immunization for the production and collection of antibodies specific to the phosphocholine diester for use in immunoassays, as suggested by Tian. One would have been motivated to develop such a method to produce such antibodies because Chasalow specifically suggests that there may be a benefit to combine spiral steroid assay with other previously proposed biomarkers for pre-eclampsia; wherein spiral steroids and/or their phosphocholine precursors might provide a basis for monitoring disease progression and permit development of improved therapeutic modalities wherein the identification of patients needing a higher level of scrutiny during the remainder of pregnancy might result in reduced maternal/fetal morbidity and mortality. One of ordinary skill in the art would have a reasonable expectation of success because Tian teaches that methods of conjugating carrier proteins to steroids, conjugation can occur directly through -NH groups present in the steroid molecule, and using said conjugates to produce antibodies (monoclonal and/or polyclonal antibodies) for use in immunoassays are known and established in the art.
Conclusion
Claims 1-20 are pending in the instant application. Claims 1-13 and 18-20 are withdrawn. Claims 14-17 are rejected. No claims are allowed.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
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