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 .
Status of the Claims
Claims 1-3, 6-10, 12-19, 22, 24-27, 30-32, 34-36, 38-39.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 16 June 2026 has been entered.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-3, 7-10, 12-19, 22, 24-27, 30-32, 34-36, and 38-39 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed structure, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. See MPEP 2163.
The inventions of independent claims 1, 14, and 25 are directed to methods comprising contacting a sample with an antibody or antibody fragment that specifically binds to apo(a), wherein the antibody or antibody fragment may comprise alternative (i) or alternative (ii), wherein antibody or antibody fragment (i) comprises the binding specificity of LPA4 such that the antibody or antibody fragment binds to KIV5, KIV7, and KIV8.
As such, the independent claims encompass a genus of antibodies and antibody fragments which are defined by their binding function.
Dependent claims 2, 9-10, 12-13, 15-19, 22, 31-32, 34-36, and 38-39 further limit different aspects and materials used in the disclosed method, but do not further limit the structure of antibody or antibody fragment (i) itself.
Dependent claim 3 further limits antibody or antibody fragment (i) by indicating that the antibody or antibody fragment comprises light chain and heavy chain CDRs of an LPA4 antibody, but does not define the CDRs, and does not indicate whether the antibody or antibody fragment (i) requires all light chain and heavy chain CDRs of the LPA4 antibody, or whether it only requires some of the CDRs.
Dependent claim 8 further limits the antibody or antibody fragment by stating that it binds to an epitope within SEQ ID NO: 17, but does not indicate whether this limitation is relevant to antibody or antibody fragment (i), (ii), or both. It is not clear from the context of the claim whether this limitation is included in or further limits an antibody or antibody fragment comprising the binding specificity of LPA4 as in embodiment (i).
Claim 26 further indicates that the antibody or antibody fragment specifically binds to Lp(a), and claim 27 further indicates that the antibody is polyclonal or monoclonal.
Claims 7, 24, and 30 further limit to an antibody or antibody fragment comprising CDRs having sequences of SEQ ID NOs: 4, 6, 8, 12, 14, and 16, but do not specify the order of CDRs or whether each occurs in the heavy chain or light chain, such that it is unclear if this limitation applies to antibody or antibody fragment (i), (ii), or both.
As such, the claims encompass a genus of antibodies or antibody fragments under alternative (i) which are defined by partial structure and binding function.
In contrast to the breadth of these claims which encompass a wide variety of structurally diverse antibodies, the instant specification provides description and reduction to practice of only two particular species of antibody (LPA4 and LPA KIV9, as shown in Table A; wherein LPA4 appears to be representative of alternative (i) and LPA KIV9 appears to be representative of alternative (ii)).
Additionally, there is a general lack of structure-function correlation for the claimed antibodies and antibody fragments. The general structure of antibodies was known in the art before the effective filing date, and it was known that the CDRs of antibodies generally control antigen binding. While CDRs are necessary for binding, they are highly diverse in structure, and their sequences do not correlate to binding in a predictable fashion. See for instance:
Goel et al. (“Plasticity within the Antigen Combining Site May Manifest as Molecular Mimicry in the Humoral Immune Response,” The Journal of Immunology (2004), 173(12):7358-7367), who made three antibodies that bind to the same 12-mer but have very different CDRs.
Lloyd et al. (“Modelling the human immune response: performance of a 1011 human antibody repertoire against a broad panel of therapeutically relevant antigens,” Protein Engineering, Design & Selection (2009), 22(3):159-168) found that on average, about 120 different antibodies in a library can bind to a given antigen.
Edwards et al. (“The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BlyS,” Journal of Molecular Biology (2003), 334:103-118) found that a library contained over 1000 antibodies that bound to a single 51 kDa protein, including 1098 unique VH and 705 VL sequences. There were 568 different CDR3 regions, indicative of high diversity.
These references indicate that there was no art-recognized correlation between the structure of an antibody or binding agent and its binding properties. A single antigen can be bound by a very large and structurally diverse genus of antibodies and binding agents. There is no common structural relationship even for antibodies that bind the same protein sequence or the same epitope. The specification does not describe the structural characteristics common to the entire genus of antibodies and antibody fragments that display the binding specificity of antibody LPA4. The specification does not provide guidance as to what essential structures of antibodies or antibody fragments would confer the necessary claimed functions and does not allow one of ordinary skill in the art to visualize or recognize the members of the genus of antibodies or antibody fragments that would be able to achieve the claimed functions.
The lack of structure-function relationship and lack of predictability in the prior art discussed above is also relevant to embodiment (ii) of the independent claims and to to claims 7, 24 and 30. Wherein the prior art shows that even very small changes to the structure of an antibody and its CDRs can significantly impact and change its binding function. As such, there is no particular evidence to support or reason to assume that any and all antibodies in the genus encompassed by claims 5, 7, 23-24 and 30 would be suitable for use in the methods as claimed. That is, there is no evidence that an antibody which comprises only some of the 6 recited CDRs or which comprises the same 6 CDRs in a different order and configuration would fulfill the necessary function of specifically binding to apo(a) or Lp(a) as required by the independent claims.
Additionally, given the lack of predictability in the art, and the breadth of variation encompassed by the claims, disclosure of antibody LPA4 in the instant application is insufficient to provide evidence of possession of the claimed genus as a whole. That is, antibody LPA4 itself is only one example of one antibody that fulfills the limitation of embodiment (i), but embodiment (i) encompasses any antibody or antibody fragment that displays the same binding specificity of LPA4. This is a much broader genus for which the essential structural elements are not disclosed in the application and for which the art is not predictable, such that disclosure of the single species is insufficient to indicate possession of the genus as a whole.
Dependent claims 2-3, 7-10, 12-13, 15-19, 22, 24, 26-27, 30-32, 34-36, and 38-39 are rejected because they depend from a rejected claim and fail to remedy its deficiencies.
Claims 1-2, 6-10, 12-19, 22, 24-27, 30-32, 34-36, 38-39 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 an antibody of embodiment (ii) comprising the 6 recited CDRs in one particular order (i.e. as shown in Table A of the specification), does not reasonably provide enablement for the entire genus of antibodies encompassed by embodiment (ii). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
A determination of enablement involves the consideration of the following factors: the breadth of the claims; the nature of the invention; the state of the prior art; level of one or ordinary skill; level of predictability in the art; amount of direction provided by the inventor; existence of working examples; and quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Regarding the breadth of the claims and the nature of the invention: the claims encompass methods of assaying Lp(a)-C (claims 1 and 14) or LDL-C (claim 25) in a sample. The claims recite use of an antibody or antibody fragment which, according to embodiment (ii) may comprise six particular CDR sequences, three of which are present in the VH domain and three of which are present in the VL domain. However, neither the independent claims nor any of the dependent claim specify that the CDRs must be present in any particular order. As such, the claims encompass a genus of antibodies where the VH and VL CDRs are present in any order.
Regarding the state of the prior art and the level of predictability of the prior art: there is a general lack of structure-function correlation for the claimed antibodies and antibody fragments. The general structure of antibodies was known in the art before the effective filing date, and it was known that the CDRs of antibodies generally control antigen binding. While CDRs are necessary for binding, they are highly diverse in structure, and their sequences do not correlate to binding in a predictable fashion. See for instance:
Goel et al. (“Plasticity within the Antigen Combining Site May Manifest as Molecular Mimicry in the Humoral Immune Response,” The Journal of Immunology (2004), 173(12):7358-7367; previously cited), who made three antibodies that bind to the same 12-mer but have very different CDRs.
Lloyd et al. (“Modelling the human immune response: performance of a 1011 human antibody repertoire against a broad panel of therapeutically relevant antigens,” Protein Engineering, Design & Selection (2009), 22(3):159-168; previously cited) found that on average, about 120 different antibodies in a library can bind to a given antigen.
Edwards et al. (“The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BlyS,” Journal of Molecular Biology (2003), 334:103-118; previously cited) found that a library contained over 1000 antibodies that bound to a single 51 kDa protein, including 1098 unique VH and 705 VL sequences. There were 568 different CDR3 regions, indicative of high diversity.
Harlow et al (Harlow, E. and Lane, D., Antibodies: A Laboratory Manual (1988) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pages 23-26), teach that the loss of a single hydrogen bond can dramatically affect the ability of an antibody to recognize a cognate antigen (Pg. 26, first full par.);
These references indicate that there was no art-recognized correlation between the structure of an antibody or binding agent and its binding properties, and that even small changes in the structure of an antibody can specifically impact its binding function.
Regarding amount of direction provided by the inventor and the existence of working examples: the specification provides description and reduction to practice of one antibody within the claimed genus (i.e. LPA KIV9 which comprises the six recited CDRs in a particular order, as shown in Table A). However given the lack of predictability in the art (which indicates that very small changes in antibody structure can drastically affect binding function), the disclosure of this single species of antibody is not sufficient to enable the entire claimed genus of antibodies, as one of ordinary skill in the art cannot predictably assume that an antibody which has the same CDRs as LPA KIV9 but in a different order will maintain the same binding properties or functionality within the claimed method.
As such, the quantity of experimentation needed to make or use the invention based on the content of the disclosure is undue. Enablement requires that the disclosure provide a reasonable level of detail which would enable one of ordinary skill in the art to understand and carry out the invention. In the instant case, such reasonable detail is lacking. There are numerous embodiments within the scope of the instant claims which are not reasonably supported or enabled by the instant disclosure or by the prior art.
For all these reasons, and when taken together with the breadth of the claims, the specification fails to teach one of ordinary skill in the art how to make and use the claimed invention in its full scope without undue experimentation.
Dependent claims 2, 7-10, 12-13, 15-19, 22, 24, 26-27, 30-32, 34-36, and 38-39 are rejected because they depend from a rejected claim and fail to remedy its deficiencies.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 3, 9-10, 12-19 are rejected under 35 U.S.C. 103 as being unpatentable over Kundu et al (WO 1993/18067; IDS entered), hereinafter Kundu ’93 in view of Tsimikas et al (Percutaneous coronary intervention results in acute increases in oxidized phospholipids and lipoprotein(a): short-term and long-term immunologic responses to oxidized low-density lipoprotein. Circulation. 2004 Jun 29;109(25):3164-70; previously cited), hereinafter Tsimikas ‘04.
Regarding claims 1, 3, 9-10, 14-16, Kundu ‘93 teaches a method of assaying Lp(a)-C in a sample (Abstract; Pg. 8, Ln. 24-28: an object of the invention is to measure the plasma Lp(a)-C concentration of patients), the method comprising:
Contacting a sample with a binding molecule that specifically binds to apo(a) to obtain an apo(a) binding molecule complex; isolating the apo(a) binding molecule complexes; performing an assay on the isolated apo(a) binding molecule complexes to measure cholesterol (Pg. 68, Ln. 10-Pg. 69, Ln. 5: production of antibody 1E1 which binds specifically to apo(a); Pg. 71, Ln. 25-Pg. 72, Ln. 19: Lp(a)-C assay comprising: antibody 1E1 coated on a microwell plate is contacted with diluted plasma sample, then washed to remove unbound components; After washing HRPO-digitonin conjugate was added to each well and incubated, then washed; solution of o-phenylenediamine (substrate) is added to each well, and then quenched after 5 min; absorbance of each well is measured on a microplate reader, and Lp(a)-C concentration was then determined from a standard curve of absorbance vs Lp(a)-C concentration).
Kundu ’93 does not specifically teach the method wherein the binding molecule comprises light chain and heavy chain CDRs of an LPA4 antibody.
Regarding claims 1, 3, 9-10, 14-16 and 24 Tsimikas ‘04 teaches measurement of Lp(a) in plasma using a chemiluminescent ELISA comprising the murine monoclonal antibody LPA4 which binds specifically to an epitope of apo(a) (Pg. 3165, Col. 1, Par. 5). Wherein the LPA4 antibody taught by Tsimikas ‘04 is understood to inherently comprise light chain and heavy chain CDRs of an LPA4 antibody.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method taught by Kundu ‘93 to comprise the LPA4 antibody taught by Tsimikas ‘04. Kundu ‘93 teaches a measurement method comprising the use of an antibody that specifically binds to apo(a). Similarly, Tsimikas ‘04 teaches a monoclonal antibody LPA4 which binds specifically to apo(a), and which can be used in an immunoassay to bind and measure Lp(a). As such, one of ordinary skill in the art would recognize from the teachings of these references that substitution of the LPA4 antibody taught by Tsimikas ‘04 for the antibody taught by Kundu ‘93 amounts to simple substitution of known elements to achieve predictable results with a reasonable expectation of success.
Regarding claims 10, 12, 15, and 17-19, Kundu ’93 further teaches that the apo(a) binding molecule may be bound to a substrate which may be a magnetic bead, and teaches that the apo(a)-antibody complex may be isolated using a magnet (Abstract: the specific lipoprotein binding agent can be bound to a solid support; Pg. 14, Ln. 33-36: the solid support may be a bead or magnetic particle; Pg. 15, Ln. 1-20: magnetic particles can be isolated from the sample using magnetic attraction).
Regarding claim 13, Kundu ’93 further teaches assay methods comprising samples from patients undergoing therapy for high cholesterol (Pg. 46, Ln. 3-5: assay evaluated with patient samples who are on lipid lowering drugs; Table 9), though it is noted that in the examples provided in the reference, these samples are used in an assay for measuring LDL-C instead of Lp(a)-C. However, Kundu ’93 further teaches that it is important to monitor and accurately measure Lp(a)-C in this population (i.e. patient undergoing therapy for high cholesterol) (Pg. 5, Ln. 21-26: it is important that Lp(a)-C correction be made in the LDL-C concentration because studies have shown that diet and drug treatment will reduce LDL-C cholesterol levels but not Lp(a) cholesterol levels and proper patient monitoring requires accurate measurement; Pg. 8, Ln. 23-28: The effect of diet and lipid lowering drugs on Lp(a)-C levels is not known. An object of the present invention is to measure the plasma Lp(a)-C concentration of patients easily and accurately to allow researchers to further investigate the relationship between Lp(a)-C concentrations and CHD).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kundu ’93 to specifically comprise the use of samples from patients undergoing therapy for high cholesterol in the method of assaying Lp(a)-C. One of ordinary skill in the art would be motivated to make this modification for the purpose of tracking and investigating the effects of lipid-lowering drugs on Lp(a)-C concentration in a patient. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because Kundu ’93 discloses similar assays using samples from this patient population.
Claims 1, 9-10, 12-15, 17-19, 22 are rejected under 35 U.S.C. 103 as being unpatentable over Kundu et al (US 2001/0051347 A1; IDS entered), hereinafter Kundu ‘01 in view of Tsimikas et al (Percutaneous coronary intervention results in acute increases in oxidized phospholipids and lipoprotein(a): short-term and long-term immunologic responses to oxidized low-density lipoprotein. Circulation. 2004 Jun 29;109(25):3164-70; previously cited), hereinafter Tsimikas ‘04.
Regarding claims 1, 14, Kundu ’01 teaches a method comprising:
Contacting a sample with an antibody or antibody fragment that specifically binds to apo(a) to obtain an apo(a)-antibody or antibody fragment complex; isolating the apo(a)-antibody or antibody fragment complexes; performing an assay on the isolated apo(a)-antibody or antibody fragment complexes to measure cholesterol (Par. 9, 18: method for determining amount of cholesterol associated with Lp(a) in a test sample comprising: contacting the sample with a monoclonal antibody or fragment thereof that specifically binds to kringle 5 of apo(a), wherein the antibody is coupled to a solid support; separating the solid support from the sample; and determining the amount of cholesterol bound to the solid support).
At Par. 66, Kundu ‘01 further teaches that methods for determining cholesterol associated with lipoproteins which may be used in the disclosed invention are well known to those of ordinary skill in the art, and that appropriate methods include those disclosed in Kundu ’93. Kundu ’93 teaches that these methods include measuring cholesterol by enzymatic colorimetric assays, as evidenced at Kundu ’93, Pg. 16.
Tsimikas ‘04 teaches measurement of Lp(a) in plasma using a chemiluminescent ELISA comprising the murine monoclonal antibody LPA4 which binds specifically to an epitope of apo(a) (Pg. 3165, Col. 1, Par. 5).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kundu to include the specific anti-apo(a) antibody LPA4 taught by Tsimikas ‘04. Kundu ‘01 teaches a method comprising the use of an antibody that binds specifically to apo(a), and teaches that an antibody that binds to an epitope of apo(a) outside of the KIV2 domain is useful in this method (Par. 9). Tsimikas ’04 discloses antibodies and fragments thereof that specifically bind to an epitope of apo(a) outside the KIV2 domain. As such, one of ordinary skill in the art would recognize that substitution of the antibody taught by Tsimikas ’04 for the antibody taught by Kundu ‘01 amounts to simple substitution of known elements to achieve predictable results with a reasonable expectation of success.
Regarding claims 9-10, 12, 15, and 17-18, Kundu ‘01 teaches the method wherein the binding molecule is linked to a substrate; wherein the substrate is an ELISA plate or a bead; and wherein the bead is a magnetic bead (Par. 18: antibody bound to a solid support; Par. 14: solid support may be a bead or magnetic particle).
Regarding claim 13, Kundu ‘01 further teaches the method wherein the sample is from a subject undergoing therapy for high cholesterol (Par. 102: cardiac patients taking lipid-lowering drugs).
Regarding claim 19, Kundu ’01 further teaches the method wherein the apo(a)-antibody complex is isolated using a magnet (Par. 14: antibody is bound to a solid support which may be a magnetic particle; Par. 18: antibody-apo(a)-solid support complex is separated from the sample; Par. 60: magnetic particles may be isolated from a sample by attraction to a magnet).
Regarding claim 22, Kundu ‘01 further teaches the method wherein the method determines the level of cholesterol in an apo(a) containing fraction of plasma (Par. 18, 22).
Claims 2, 25-27, 31-32, 34-36, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Kundu et al (US 2001/0051347 A1; IDS entered), hereinafter Kundu ‘01 in view of Tsimikas et al (Percutaneous coronary intervention results in acute increases in oxidized phospholipids and lipoprotein(a): short-term and long-term immunologic responses to oxidized low-density lipoprotein. Circulation. 2004 Jun 29;109(25):3164-70; previously cited), hereinafter Tsimikas ’04 as applied to claims 1 and 14 above, and further in view of Kundu et al (WO 1993/18067; IDS entered), hereinafter Kundu ‘93.
Regarding claims 2, 25 and 31, Kundu ‘01 teaches a method comprising:
Contacting a plasma sample with a composition or article of manufacture comprising a binding agent linked to a carrier, wherein the binding agent specifically binds to Lp(a), and wherein the carrier separate bound Lp(a) from a soluble fraction of the plasma (Par. 18).
Regarding claims 2 and 31, Kundu ’01 further teaches measuring the amount of cholesterol in the Lp(a)-C fraction to obtain and Lp(a)-C value (Par. 18).
Kundu ‘01 does not specifically disclose measuring the amount of cholesterol in the soluble fraction to obtain an LDL-C value.
Regarding claims 2, 25 and 31, Kundu ’93 teaches measuring the amount of cholesterol in a soluble fraction of plasma after removal of an Lp(a)-C fraction of plasma to thereby obtain an LDL-C value, wherein isolation and removal of the Lp(a)-C fraction from the sample allows for a more accurate determination of LDL-C levels (Pg. 5, Ln. 21-34: it is important that the Lp(a)-C correction be made in the LDL-C concentration because studies have shown that diet and drug treatment will reduce LDL-C levels but not Lp(a)-C levels, and proper patient monitoring requires an accurate measurement of LDL-C levels. This is particularly true for patient with elevated Lp(a). In such patients, the LDL-C values will be erroneous if no correction is made for Lp(a) cholesterol; Pg. 9, Ln. 7-11).
Both Kundu ’01 and Kundu ’93 teach that the amount of cholesterol in a particular fraction of a sample can be measured using an absorbance reading (Kundu ‘01, Par. 104-106; Kundu ’93, Pg. 53, Ln. 35-36, Pg. 64, Ln. 29-32, Pg. 72, Ln. 14-15).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method taught by Kundu ‘01 to further include measuring absorbance of the soluble fraction of plasma after removal of the Lp(a)-C fraction in order to obtain an LDL-C value. One of ordinary skill in the art would be motivated to make this modification for the purpose of obtaining a corrected LDL-C value which is more accurate because it does not comprise any Lp(a)-C, wherein this more accurate LDL-C value is useful for prognosis and monitoring, and wherein isolated values of both Lp(a)-C and corrected LDL-C are more useful in evaluating and monitoring cholesterol levels and treatments and associated risks of cardiovascular disease. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because both Kundu ‘01 and Kundu ’93 disclose methods of evaluating levels of cholesterol associated with specific lipoproteins using similar reagents and assays.
Regarding claims 26-27, Kundu ’01 further teaches the method wherein the binding agent is a polyclonal or monoclonal antibody that specifically binds to Lp(a) (Par. 18).
Regarding claim 32, Kundu ‘01 further teaches the method comprising measuring the amount of total cholesterol in the sample or in a corresponding sample prior to contacting the sample with the composition or article of manufacture to obtain an LDL-C value (Par. 102).
Regarding claim 34, Kundu ‘01 does not explicitly teach the method wherein Lp(a)-C value is subtracted from the total cholesterol value to obtain a corrected LDL-C value.
Regarding claim 34, Kundu ’93 teaches a method wherein the Lp(a)-C value is subtracted from the total cholesterol value to obtain a corrected LDL-C value (Pg. 5, Ln. 4-14).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kundu ‘01 to further comprise subtracting the Lp(a)-C value from the total cholesterol value to obtain a corrected LDL-C value, as disclosed by Kundu ’93 for the benefit of having a corrected LDL-C value for proper patient monitoring and evaluation (Kundu ’93, Pg. 5, Ln. 21-34; Pg. 9, Ln. 7-11). Wherein this value can also be compared to the LDL-C value obtained in claim 25 to confirm the accuracy or observe variation in the measurements. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because both Kundu ’01 and Kundu ’93 are directed to methods of measuring levels of cholesterol associated with specific lipoproteins using similar reagents and assays.
Regarding claims 35-36, Kundu ‘01 further teaches the metho wherein the composition comprises a bead linked to the binding agent which may be a magnetic bead (Par. 14).
Regarding claims 38-39, Kundu ‘01 further teaches the method wherein the article of manufacture is a substrate comprising the binding agent, wherein the substrate may be a microwell plate (Par. 14, 49, 60, 104).
Subject Matter Free of Prior Art
Claims 6-8, 24, and 30 are rejected as described above, however they appear to be free of the prior art.
The closest prior art is Kundu’93, Kundu ’01 and Tsimikas ’04 as described in the rejections above. However, the prior art does not teach the method comprising an antibody comprising an amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 10; does not teach an antibody comprising CDR regions of SEQ ID NO: 4, 6, 8, 12, 14, and 16; and does not teach the method wherein the antibody or antibody fragment binds to an epitope within SEQ ID NO: 17.
Response to Arguments
Applicant’s arguments filed 16 June 2026 have been fully considered.
Regarding the 112(a) rejection, Applicant argues that there is adequate written description in the disclosure to support the genus of antibodies in the instant claim and cites recently decided case law Teva Pharmaceuticals International GmbH v. Eli Lilly & Co., No. 2024-1094 (Fed. Cir. Apr. 16, 2026) which states “a reasonable jury could have found that anti-CGRP antagonist antibodies themselves and methods of making them were well known, replete, or extensively described in the prior art”. Applicant argues that the instant claims are directed to the use of an antibody comprising the binding specificity of LPA4, and that the specification provides information about how to obtain and generate an LPA4 antibody. These arguments are not persuasive.
The instant claims encompass a genus of antibodies which is defined by a particular and specific binding function. Although applicant argues that this is analogous to case law regarding anti-CGRP antagonist antibodies for which methods of making are well known, replete, or extensively described in the prior art, the examiner does not agree with this assertion. Applicant indicates support for this argument in Tsimikas ’04 and in the instant specification at Par. 79. Tsimikas ’04 describes the method of making the LPA4 antibody. Specification Par. 79 describes generic procedures for the production of antibodies and indicates that nucleotide and polypeptide sequences useful in the generation of anti-Lp(a) antibodies and fragments thereof are provided in Table A. However, it is not clear from the information provided what portions or fragments of the sequence displayed in Table A are or are not useful in producing anti-Lp(a) antibodies, and it is not clear whether all anti-Lp(a) antibodies produced will have the particular binding specificity of the LPA4 antibody as claimed. Therefore, the information provided indicates only one particular species of antibody which has a known structure and which is known to have the particular binding specificity of an LPA4 antibody as claimed, and that is the LPA4 antibody itself.
The disclosure of one particular species of antibody and the method of producing that one particular species of antibody does not indicate that methods of making the entire claimed genus of antibody are well known, replete, or extensively described in the prior art.
Additionally given the unpredictability of the art and the lack of structure-function relationship between an antibody’s structure and its binding function, as described in the rejection above, the disclosure of a single species of antibody which meets the claimed functional requirements is insufficient to demonstrate possession of the entire genus as claimed, therefore there is inadequate written description. See, e.g. MPEP 2163(II)(A)(3)(a)(ii): Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. 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.
The 103 rejections reliant on Tsimikas ’20 are withdrawn in view of Applicant’s declaration under 37 CFR 1.130(a) which is sufficient to establish that Tsimikas ’20 is not available as prior art under 35 U.S.C. 102(b)(1)(A).
Regarding the 103 rejections reliant on Kundu ’93 in view of Tsimikas ‘04:
Applicant argues that this combination of prior art does not teach alternative (ii) of the claims. This argument is not persuasive because the prior art is not relied upon to teach alternative (ii) of the claims, but rather is relied upon to teach alternative (i) of the claims.
Applicant argues that Kunud ’93 uses its own antibodies (e.g. antibody 1E1), not LPA4. Applicant argues that there is no teaching or suggestion in Kundu’93 to look to LPA4 specifically and that the references do not provide a specific motivation to combine them. This argument is not persuasive because the rejection is based on a simple substitution rationale which does not rely on specific motivation to combine the references, but rather relies on the finding that one of ordinary skill in the art could have substituted one known element for another to obtain predictable results with a reasonable expectation of success, as discussed in MPEP 2143(I)(B).
Applicant argues that Tsimikas ’04 uses LPA4 as a detection antibody in a sandwich ELISA to measure Lp(a) particle concentration (i.e. to quantify how much Lp(a) is present in plasma), while the claimed methods, by contrast, use the antibody in a fundamentally different role: as an immunocapture agent to isolate Lp(a) from plasma, and argues that the simple substitution rationale does not account for this fundamental difference in the role of the antibody and the nature of the analyte. This argument is not persuasive. Tsimikas ’04 is not relied upon to teach the use of the antibody in exactly the same role. Kundu ‘93 teaches a measurement method comprising the use of an antibody that specifically binds to apo(a). Similarly, Tsimikas ‘04 teaches a monoclonal antibody LPA4 which binds specifically to apo(a), and which can be used in an immunoassay to bind and measure Lp(a). As such one could have substituted one antibody for the other to achieve predictable results with a reasonable expectation of success, as is required for an argument of simple substitution, as discussed in MPEP 2143(I)(B).
Applicant argues that neither Kundu’93 nor Tsimikas ’04 provides guidance that LPA4 would be suitable or advantageous for cholesterol quantification. Applicant argues that despite the availability of both LPA4 (since 2004) and immunocapture based Lp(a) cholesterol methods (since 1993), the specific combination of using LPA4 as an immunocapture antibody for direct measurement of Lp(a) cholesterol content has not been achieved prior to the present invention. This argument is not persuasive. Arguments directed to the age of reference as not persuasive of the unobviousness of their teachings, as discussed in MPEP 2145(VIII).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELLIS LUSI whose telephone number is (571)270-0694. The examiner can normally be reached M-Th 8am-6pm ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached at (571) 272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ELLIS FOLLETT LUSI/Examiner, Art Unit 1677
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677
Prosecution Insights