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 .
Applicants are informed that further examination of the instant application will be conducted by Examiner Blumel. Contact information can be found at the end of this Office action.
Priority
Acknowledgment is made of applicant's claim for foreign priority under 35 U.S.C.
119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR
1.55. The earliest potential effective filing date of the claimed inventions is 09-25-2019
based on the filing date of the foreign priority application EP19306200.7.
Election/Restrictions
Applicant's election without traverse of Group I, claims 26-43 and the species
Apolipoprotein A1 (ApoA1) in the reply filed on 05-13-2025 is acknowledged.
Claims 44 and 45 are withdrawn from further consideration pursuant to 37 CFR
1.142(b) as being drawn to a nonelected invention, there being no allowable generic or
linking claim. Election was made without traverse in the reply filed on 05-13-2025.
Status of Claims
Claims 27-29, 36, 39-43 and 46 are examined on their merits. Claim 46 is newly presented. Claims 44 and 45 are withdrawn.
Information Disclosure Statement
The Information Disclosure Statements filed on 6/30/26 is acknowledged and have been considered.
The listing of references in the specification is not a proper information disclosure
statement. 37 CFR 1.98(b) requires a list of all patents, publications, applications, or
other information submitted for consideration by the Office, and MPEP § 609.04(a),
subsection I. states, "the list may not be incorporated into the specification but must be
submitted in a separate paper." Therefore, unless the references have been cited by the
examiner on form PTO-892, they have not been considered.
Withdrawn objection to the Drawings in view of amendment
Claim Objections
(Withdrawn in view of amendments) Claim 29 is objected to because of the following informalities: " a third antibody raised against antibody specific for should read "against an antibody" or "against antibodies".
(Withdrawn in view of amendments) Claim 40 is objected to because it appears that "Apo1" should read "ApoA1" to correspond with the language used in the other claims.
Appropriate correction of all claim rejections is required.
Claim Rejections - 35 USC § 112(b)
Claims 26-43 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.
(Withdrawn in view of claim cancellation) Claim 26.
(Withdrawn in view of claim amendments) Claim 27
(Withdrawn in view of claim amendments) Claim 28
(Withdrawn in view of claim amendments) Claim 29
(Withdrawn in view of claim cancellation) Claim 35
(Withdrawn in view of claim cancellation) Claim 35
Claim Rejections - 35 USC § 101
(Withdrawn in view of claim cancellation and claim amendments) Claims 35-37 are rejected under 35 U.S.C. 101.
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.
(New Rejection) Claims 27-29, 36, 38-42 and 45 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 a method of detecting a flavivirus NS1-ApoA1 complex by using an anti-NS1 monoclonal antibody 17A12 and an anti-ApoA1 polyclonal NB400-147 or monoclonal antibody ab27630, does not reasonably provide enablement for a method of detecting a flavivirus NS1-ApoA1 complex by using an anti-NS1 antibody and an anti-ApoA1 antibody. 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 the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The claimed invention is drawn to an in vitro method for detecting or quantitating a complex formed by dimers of a Dengue virus non-structural protein 1 (NS1) bound at the surface of plasma High Density Lipoprotein (HDL) particles in a blood sample obtained from a subject (human), comprising
a. contacting the blood sample with an antibody specific for the dengue virus NS1 to form a first immunoreaction product;
b. contacting said first immunoreaction product with an antibody specific for Apolipoprotein A1 (ApoA1) to form a second immunoreaction product;
C. detecting the presence of the second immunoreaction product, and optionally;
d. quantitating the complex formed by NS1 and plasma HDL particles.
Wherein the presence or quantity of the complex is determined by capture ELISA using the anti-NS1 coated on a solid support, a third antibody raised against the antibody specific for ApoA1 and conjugated to a suitable label is used for detecting the presence of the second immunoreaction product. The method is performed on a blood sample obtained during a primary or acute infection of the subject or samples are obtained at different times during an infection. The presence of flavivirus NS1 and plasma HDL particles in the sample is indicative of a flaviviral infection. The method is repeatedly carried out on a blood (plasma or serum) sample obtained from said subject to quantitate complex of NS1-ApoA1 positive lipoprotein particles. The method is repeatedly carried out on a blood sample obtained from said subject to quantitate complex of flaviviral NS1-Apo1 positive lipoprotein particles and further quantitate complex of flaviviral NS1-ApoE positive lipoprotein particles, and/or complex of flaviviral NS1-ApoB positive lipoprotein particles.
Applicants have tested the ability of anti-NS1 monoclonal antibody 17A12 to bind to dengue NS1 and anti-ApoA1 polyclonal NB400-147 or monoclonal antibody ab27630 in the detection of ApoA1 and NS1-ApoA1 complexes. Furthermore, since the claimed invention does not recite any specific structure (i.e., the 6 CDR sequences of the variable domains or full-length variable domains) for the anti-NS1 and anti-ApoA1 antibodies being used in the method of one of ordinary skill in the art would be exposed to undue experimentation to determine if such an undefined antibody can bind to dengue NS1 or ApoA1.
Thus, the claims are directed to a broad class of antibodies, only defined by its function and amino acid sequences that might be required or might be fragments thereof or variants thereof. However, relative to the claimed openness to generic antibodies, the specification does not give one of ordinary skilled in the art enough information to choose candidate antigen binding structures from the vast number of options that fall within the fragments of the claimed antibodies, and therefore required scientists to engage in a great deal of experimentation and failure. “That is not enablement”—it is a “hunting license.”
In Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR. This decision reaffirmed the prior decision made by the Federal District Court in Amgen Inc. v. Sanofi, Aventisub LLC., 987 F.3d 1080 (Fed. Cir. 2021).
The Court clarified that the specification does not always need to "describe with particularity how to make and use every single embodiment within a claimed class." Id. at 610-11. However, "[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class….The more one claims, the more one must enable." Id.
The specification may require a reasonable amount of experimentation to make and use the invention and what is reasonable will depend on the nature of the invention and the underlying art. For example, "it may suffice to give an example (or a few examples) if the specification also discloses some general quality … running through the class that gives it a peculiar fitness for the particular purpose" and "disclosing that general quality may reliably enable a person skilled in the art to make and use all of what is claimed, not merely a subset." Id. at 611 (internal quotations omitted). However, the Supreme Court found that Amgen failed to enable all that it claimed, even if allowing for a reasonable degree of experimentation. Id. at 613; see also Baxalta Inc. v Genentech, Inc., 81 F.4th 1362, 1367, 2023 USPQ2d 1103 (Fed. Cir. 2023) ("[t]he facts of this case are more analogous to—and are, in fact, indistinguishable from—those in Amgen. We do not interpret Amgen to have disturbed our prior enablement case law, including Wands and its factors."). Moreover, "[w]e see no meaningful difference between Wands' ‘undue experimentation’ and Amgen's ‘[un]reasonable experimentation’ standards. Id. at footnote 4. See also 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), which explains that regardless of the technology the Wands factors should be used when assessing enablement.
However, while the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class which included "a ‘vast’ number of additional antibodies" that Amgen had not described by their amino acid sequences. Id. at 613. The Court found that Amgen sought to monopolize an entire class by their function, even though that class was much broader than the 26 exemplary antibodies disclosed by their amino acid structure. Id. at 613.
In Amgen Inc. v. Sanofi, Aventisub LLC, 987 F.3d 1080 (Fed. Cir. 2021), which the Supreme Court affirmed, the Federal Circuit explicitly applied the Wands factors to assess whether the specification of Amgen’s patent provided sufficient enablement, for purposes of 35 U.S.C. 112(a), to make and use the full scope of the claimed invention. The court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. See also the following cases across various technology areas: McRO, Inc. v. Bandai Namco Games Am. Inc., 959 F.3d 1091, 2020 USPQ2d 10550 (Fed. Cir. 2020); Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380, 107 USPQ2d 1273 (Fed. Cir. 2013); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340 (Fed. Cir. 2019); and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149, 2019 USPQ2d 415844 (Fed. Cir. 2019).
Amgen attempted to claim an entire class of compounds by their function, namely antibodies that bind to the “sweet spot” of PCSK9 thereby inhibiting it from binding to LDL, while only describing 26 amino acid sequences in its specification. The two processes, the “roadmap” and “conservative substitution” did not save Amgen. According to the Court, these amounted to “little more than two research assignments” which forced scientists to conduct “painstaking experimentation” to see what worked. (citing Incandescent Lamp). The Court therefore held that Amgen’s specification did not enable the claims.
This case is akin to the issue in Amgen Inc. v. Sanofi, Aventisub LLC, in which the court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Sanofi-Aventisub at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. While the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class that included “a ‘vast' number of additional antibodies” that Amgen had not described by their amino acid sequences. Id. at 1256. The Supreme Court found that Amgen sought to monopolize an entire class of antibodies by their function, which was much broader than the 26 exemplary antibodies disclosed by their amino acid structure.
The instant claims are directed to a class of antibodies that include “a ‘vast’ number of antibodies comprising an undefined structure and still be able to bind the dengue NS1 or ApoA1, in view of teachings for the specification. It would be necessary to first generate and then screen each candidate antibody and fragments thereof, with the recited function to determine whether it met the functional limitations of being able to bind dengue virus NS1 and ApoA1 and a complex formed between the two. The Federal Circuit concluded that there was a lack of enablement, which was affirmed by the Supreme Court in Amgen.
With regard to the antibodies used in the instant method, applicants have tested the ability of anti-NS1 monoclonal antibody 17A12 to bind to dengue NS1 and anti-ApoA1 polyclonal NB400-147 or monoclonal antibody ab27630 in the detection of ApoA1 and NS1-ApoA1 complexes.
The instant claims simply direct skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the antigen binding CDRs they elected to disclose and that “[u]nder Amgen, such random trial-and-error discovery, without more, constitutes unreasonable experimentation that falls outside the bounds required by § 112(a).” Id. at *8, *10.
The Supreme Court’s 2023 decision in Amgen v. Sanofi, which mainly involves the enablement requirement, states that “where a patentee purports to invent an entire genus, it must enable the entire genus”; “disclosing how to produce some antibodies that perform a specified function is not equivalent to disclosing how to produce all such antibodies – and it is the latter that petitioners claim as their invention”; S. Ct.
The specification does not reasonably provide enablement to use the invention of claims 27-29, 36, 38-42 and 45 as it is currently written. The specification does reasonably provide enablement to make and use the invention as discussed above.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary, the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
In addition, any CDR mutation, which can happen when you recombine all these CDRs into different species is not predictable. This is evidenced by the fact that even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff (Proc Natl Acad Sci USA 1982 Vol 79 page 1979). Rudikoff teaches that the alteration of a single amino acid in a single CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (entire article, Abstract).)
Moreover, claims not containing elements critical or essential to the practice of the invention, such as antibodies not having all of the relevant functional complementarity determining regions (CDRs) in the proper site on an appropriate antibody heavy or light chain framework, are not enabled by the disclosure. See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976).
Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
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 inventior 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.
This application currently names joint inventors. In considering patentability of the
claims the examiner presumes that the subject matter of the various claims was
commonly owned as of the effective filing date of the claimed invention(s) absent any
evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to
point out the inventor and effective filing dates of each claim that was not commonly
owned as of the effective filing date of the later invention in order for the examiner to
consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2)
prior art against the later invention.
(Prior rejection is withdrawn in view of amendments) Claims 26-29, 32, 39, and 41-43 are rejected under 35 U.S.C. 103 as being unpatentable over Gutsche et al (PNAS 2011- see attached form 892), Hermann et al (PLoS Neglected Tropical Diseases 2014- see attached form 892), and Li et al (PLoS One 2013- included on IDS).
(Prior rejection withdrawn in view of amendments) ) Claims 30, 31, 33-38, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Gutsche et al, Hermann et al, and Li et al as applied to claim 26 above and further in view of Biswas et al (PLoS Neglected Tropical Diseases 2015- see attached form 892) as evidenced by Jonas and Phillips (Chapter 17
Biochemistry of Lipids, Lipoproteins and Membranes, Fifth Edition 2008- see
attached form 892).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BENJAMIN P BLUMEL whose telephone number is (571)272-4960. The examiner can normally be reached M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached at (571) 270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671
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