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 .
Applicant’s amendment, filed on 4/1/2026, is acknowledged.
Claims 11-13, 17, and 23-25 are cancelled.
Claims 1-10, 14-16, 18-22, and 26-29 are currently pending.
Election/Restrictions
Applicants’ election with traverse of Group I, claims 1-10, 14-16, and 18-22, directed to antiviral and immunogenic compositions comprising at least one anti-UL141 antibody and a modified Fc region, and the Species of: i) the VH and VL of SEQ ID NO: 4 and 12; ii) the S239D Fc mutation; and iii) the IgG isotype, filed on 4/01/2026, is acknowledged.
The traversal is on the grounds that the Tomasec et al. (Nat Immunol. 2005 Feb;6(2):181-8. doi: 10.1038/ni1156. Epub 2005 Jan 9, in Restriction Requirement mailed on 2/02/2026) reference does not teach that UL141 is expressed early in the viral life cycle, nor that anti-UL141 antibodies would be effective therapeutics in treating a HCMV infection via NK cell mediated ADCC, and that point mutations that increase ADCC is important for efficacy against HCMV infection.
This has been found to be not persuasive. The special technical feature in the Groups of Invention require at least one monoclonal antibody that binds to UL141 and a modified Fc region. As stated in the Restriction Requirement mailed on 2/02/2026, Tomasec et al. (supra) in view of Mimoto et al. (MAbs. 2013 Mar-Apr;5(2):229-36. doi: 10.4161/mabs.23452. Epub 2013 Feb 13, in Restriction Requirement mailed on 2/02/2026). Teaches an anti-UL141 monoclonal antibody with a Fc mutation that increases ADCC, which is antibody-mediated cellular cytotoxicity. One with ordinary skill in the art would appreciate that the UL141 antibody of Tomasec et al. would have its antibody-mediated cellular cytotoxicity increased by the point mutations taught by Mimoto et al.
The requirement is still deemed proper and is therefore made FINAL.
The elected species of Fc mutation, S239D has the effect of enhancing Fc region binding to CD16 and therefore enhancing ADCC (Specification pg. 10, lines 4-9). This does not have the function of increasing serum half-life, and therefore claims 15 and 16 read on unelected species of Fc region modifications.
Claims 15, 16, and 26-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions and/or Species.
Claims 1-10, 14, and 18-22 are under examination as reading on an anti-viral or immunogenic composition comprising at least one monoclonal anti-UL141 antibody comprising the VH and VL of SEQ ID NO: 4 and 12, respectively, wherein the Fc region comprises the S239D mutation.
Priority
Applicant’s claim for the benefit of a prior-filed GB Application 2101066.5, filed January 27, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 7/26/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner in its entirety.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
The Specification discloses multiple instances of linker sequences that are over 3 residues in length on pg. 38, line 32; pg. 39, lines 3, 11, 19, 29, 30, 33, 34; and pg. 40, lines 2, 3, 6, and 9.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because the abstract uses language that can be implied, including “[t]he invention relates to…”, as well as legal phraseology including “said”. 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 use of the terms:
Cytovene® (pg. 2, line 20; );
Valcyte® (pg. 2, line 20; );
Cytotect® (pg. 12, line 25; pg. 28, lines 28 and 31; pg. 29, lines 1 and 27; pg. 30, lines 3, 11, 17, and 28; pg. 31, line 26; pg. 32, line 9; pg. 33, lines 6 and 8; pg. 34, line 23; pg. 44, line 30; pg. 48, line 28; pg. 49, lines 16 and 30; pg. 50, lines 8 and 12);
NEBuilder® (pg. 38, lines 1 and 13);
Expi293™ (pg. 38, lines 5 and 8; pg. 41, lines 24 and 28);
GeneArt® (pg. 38, line 11);
Pluronic® (pg. 41, line 27);
TrypLE™ (pg. 42, line 21);
GIBCO™ (pg. 42, line 22);
GolgiStop™ (pg. 42, line 23);
LIVE/DEAD™ (pg. 42, line 28);
Cytofix/Cytoperm™ (pg. 42, line 31);
Attune™ (pg. 42, lines 33 and 34);
Triton™ (pg. 43, line 11);
Criterion TGX™ (pg. 43, line 28);
which are trade names or marks 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 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 1-10, 14, and 18-22 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 anti-viral or immunogenic compositions comprising at least one monoclonal anti-UL141 antibody with the structure (defined by their VH and VL sequences) of the antibody clones B2, C3, D3, E5, G2, G4, G4, and G12 and the function of “binds UL141 protein”, does not reasonably provide enablement for a broad genus of anti-UL141 monoclonal antibodies with a partial structure at best and the function of “binds UL141 protein” (claims 1-10, 14, and 18-22); OR immunogenic compositions or vaccines comprising antibodies (claim 20). 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 and use 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.
Breadth of claims and nature of invention:
Claims 1-5, 9, 14, and 18-22 encompass a broad genus of at least one monoclonal antibody with no recited structure and the function of “binds UL141 protein”, which encompasses millions to billions of antibody structures, defined by their CDRs, with the recited function.
Claims 6-8 encompass a broad genus of antibodies with at least one of the recite variable region sequences in claim 6, or variants with up to 15% sequence variation in the recited variable region sequences, including in the CDR regions that are critical for binding, all with the recited function of “binds to UL141 protein”. Claim 10 encompasses a broad genus of antibodies with any combination of VH and VL sequences recited in claim 6, or variants with up to 15% sequence variation in the recited variable region sequences, including in the CDR regions that are critical for binding, all with the recited function of “binds to UL141 protein”. These claims encompass millions to billions of different antibody structures, defined by their CDR regions, with the function of “binds to UL141 protein”.
For example, claim 10 encompasses monoclonal antibodies comprising the elected VH and VL or SEQ ID NO: 4 and 12, respectively, and variants in these sequences with up to 15% variation. Regarding the VH alone (SEQ ID NO: 4), the total number of variants of a polypeptide having a specific number of amino acid substitutions can be calculated from the formula:
N
!
*
19
A
N
-
A
!
A
!
Where N is the length in amino acids of the reference polypeptide and A is the number of allowed substitutions. For a polypeptide (instant SEQ ID NO: 4) that is 107 residues in length with 16 allowed substitutions (0.15*107≈16), there would be
107
!
*
19
(
16
)
107
-
16
!
16
!
Which is approximately 5.77x1047 VH variants alone, all with the function of “binds to UL141”
The specification discloses isolation of antibody clones from PBMCs of healthy HCMV seropositive donors, followed by modification of the Fc regions to enhance binding to FcγRIII (pg. 37, lines 5-25).
Amount of direction and existence of working examples:
The instant specification discloses the isolation and identification of eight different mAb clones that have the function of “binds to UL141” (Fig. 3D and pg. 30), which are B2, C3, D3, E5, G2, G3, G4, and G11. Each of these monoclonal anti-UL141 antibodies has a specific VH sequence paired with a specific VL sequence to give rise to functional anti-UL141 binding antibodies (pg. 4-7, SEQ ID NO: 1-16).
Level of predictability, state of prior art, and quantity of experimentation needed:
Regarding the broadly claimed genus of anti-UL141 monoclonal antibodies with a partial structure at best and the function of “binds UL141 protein” (claims 1-10, 14, and 18-22);
The claims are directed to monoclonal antibodies with no recited structure (claims 1-5, 9, 14, and 18-22), or a partial structure at best (6-8 and 10), with the function of “binds to UL141”, all of which encompass broad genera of millions to billions of different antibody structure with the recite function.
However, the specification did not give the skilled in the art enough information to choose candidate antigen binding structures from the vast number of options of millions of candidates, and therefore required scientists to engage in a great deal of experimentation and failure. “That is not enablement”—it is a “hunting license.”
The specification discloses eight different anti-UL141 monoclonal antibodies, defined by their VH and VL sequences, with the function of “binds to UL141”.
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.
In the instant case, the claims are directed to a broad class of monoclonal antibodies with a partial structure at best and the function of “binds to UL141”, while the instant specification discloses eight specific working examples of monoclonal antibodies with this recited function.
The instant claims are directed to classes of monoclonal antibodies that include “a ‘vast’ number” of additional structures (i.e., amino acid sequences of all 6 CDR regions that are necessary for antigen binding) in which the instant specification fails to describe. It would be necessary to first generate and then screen each candidate antibody to determine whether or not it met the function limitations of “binds to UL141”. The Federal Circuit concluded that there was a lack of enablement, which was affirmed by the Supreme Court in Amgen.
The instant specification does not disclose any common structural feature delineating which other antibody structures would have the function of “binds to UL141”. The only structure-function relationship guidance the specification provides is to disclose individual examples of anti-UL141 monoclonal antibody clones B2, C3, D3, E5, G2, G3, G4, and G11.
The instant claims simply direct skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the antibody structures 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 specification discloses only eight antibodies within the claimed scope. It is unlikely that antibodies or fragments thereof as defined by the claims which may contain less than the full complement of CDRs from the heavy and light chain variable regions of each of the monoclonal antibody clones B2, C3, D3, E5, G2, G3, G4, and G11 antibodies fused to framework sequences have the required binding function. The specification provides no direction or guidance regarding how to produce monoclonal antibodies as broadly defined by the claims. Undue experimentation would be required to produce the invention commensurate with the scope of the claims from the written disclosure alone. Further, the specification does not teach that a functional antibody can be obtained by replacing the CDR regions of an acceptor antibody with the less than all the 6 CDRs sequences of a donor antibody.
Furthermore, neither the specification, nor the prior art provides any examples to support the premise of mixing and matching a HCDR or LCDR of the VH/VL of different antibodies would result in antigen binding. The prior art does not support a definition of an antibody structure by mixing and matching the HCDR1-3 sequences of a VH and/or LCDR sequences of a VL of different antibody clones would result in functional UL141 binding. The specification fails to show that all HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3 of the 7 anti-UL141 antibodies B2, C3, D3, E5, G2, G3, G4, and G11, are equivalent. The specification fails to establish that, for example, by replacing at least one different CDR of the antibody clones B2, C3, D3, E5, G2, G3, G4, or G11, maintains specific UL141 binding. Mixing and matching different CDRs from different anti-UL141 antibodies have not been shown to lead to specific UL141 binding. Such teachings were not made part of the specification at the time the invention was made.
Additionally, instant claims 6-8 and 10 encompass (but does not exemplify) antibody VH and VL sequences with modifications of up to 15% (deletion/addition/substitution) to the claimed VH and VL sequences, including the CDR regions critical for antigen binding. There is no teaching identifying what amino acids can be varied within the VH-CDRs and/or VL-CDRs antibody regions and still retain the function of binding to UL141. Brown et al. (J. Immuno. 1996 May, 3285-91 at 3290 and Tables 1 and 2) describes how a one amino acid change in the VH CDR2 of a particular antibody was tolerated whereas, the antibody lost binding upon introduction of two amino changes in the same region. Vajdos et al. (J. Mol. Biol. 2002, Jul 5, 320(2):415-28 at 416) teach that amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. The scope of the claims encompasses antibodies with VH or VL that encompass variation (addition, deletion, substitution) in their CDRs. The prior art discloses that 6 CDRs as being essential structure of antibody's binding site, and thus when intact, would provide enough structure to define the antibody's binding site (structure/function correlation) e.g., where amino acid substitutions can be made so as to change (e.g., 6CDR's) or retain (e.g., constant or variable framework) antigen binding. Neither the prior art nor applicant's disclosure defines sufficient representative antibodies and/or sufficient structure/function correlation between modifying the VLCDRs or VHCDRs regions of the disclosed antibodies and the retention of a specific binding antibody that binds to HCMV UL141 to satisfy the enablement requirement for the claims.
Applicant is relying upon certain biological activities such as antibodies that target UL141 and a limited number of species with defined structures (e.g. amino acid sequences) to support an entire genus of diverse and structurally unrelated antibody structures. Yet the instant specification does not provide sufficient guidance and directions as to the structural features of the polypeptide structures and the correlation between the structure and the desired antigen binding and function.
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.
Additionally, in its recent decision in Baxalta Inc. v. Genentech, Inc., No. 2022-1461, 2023 WL 6135930 (Fed. Cir. Sept. 20, 2023) the Federal Circuit found the facts of this case to be "materially indistinguishable from those in Amgen." Baxalta, 2023 WL 6135930, at *4. According to the Federal Circuit, claim 1 covers "millions of potential candidate antibodies" (id.) that bind to Factor IX/IXa and increase the procoagulant activity of Factor IXa. The court, however, noted that the specification discloses the amino acid sequence of just 11 of those antibodies. And like the roadmap in the patents at issue in Amgen, "the '590 patent's roadmap simply directs skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the [11] antibodies they elected to disclose." (Id.) Missing from the specification, according to the Federal Circuit, was "'a quality common to every functional embodiment' ... that would allow a skilled artisan to predict which antibodies will perform the claimed functions" (id.; quoting Amgen Inc. v. Sanofi., 598 U.S. 594, 614 (2023)), such as a common structural or other feature that would allow the antibodies to perform the claimed functions, or an explanation as to why the 11 antibodies do so and others do not. (Baxalta, 2023 WL 6135930, at *4). And the Federal Circuit was not persuaded by Baxalta's argument that its disclosed hybridoma-and screening process "predictably and reliably generates new claimed antibodies every time it is performed" (id.), because "it is undisputed that to practice the full scope of the claimed invention, skilled artisans must make candidate antibodies and screen them to determine which ones perform the claimed functions." (Id.).
Regarding the claimed immunogenic compositions or vaccines comprising anti-UL141 monoclonal antibodies:
The instant specification does not disclose any working examples of using anti-UL141 antibodies as a vaccine to induce an immunogenic response (i.e., adaptive immunogenic response) to hCMV. Additionally, the prior art teaches that monoclonal antibodies can act as a form of passive immunization, and not as an active immunogen such as a vaccine. Slifka et al. (Plotkin's Vaccines. 2018:84–95.e10. doi: 10.1016/B978-0-323-35761-6.00008-0. Epub 2017 Jul 17) teaches that maternal antibodies can act as a form of natural passive immunity for offspring (pg. 84 and 85). Slifka et al. further teaches that both monoclonal antibodies and polyclonal antibodies can be harnessed as therapeutics for passive immunity against a variety of pathogens (pg. 86-87).
Neither the instant specification nor the prior art provides sufficient guidance to enable one with ordinary skill in the art to create immunogenic compositions or vaccines comprising monoclonal antibodies, as the prior art teaches that such antibodies act as a form of passive immunization and not active immunization. Undue experimentation would be required to generate monoclonal antibodies that could act as vaccines given the limited guidance in the specification and the prior art.
The specification does not reasonably provide enablement to make and use the invention of instant claims 1-10, 14, and 18-22. The specification does enable one with ordinary skill to make the antibody clone discussed supra.
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.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3 and 4 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.
Claims 3 and 4 are indefinite because the claims recite amino acid position numbers (i.e., “position 234” or “L234Y”) without a corresponding reference amino acid sequence in the claims. It is currently unclear which amino acid sequences the recited residue numbers refer to. It is recommended to amend the claims to recite a reference sequence in the claims, or to recite an established antibody amino acid residue numbering system, to overcome this issue.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 1-4, 9, 14, and 18, 21, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Weekes et al. (U.S. PGPub 20180327482) in view of Mimoto et al. (MAbs. 2013 Mar-Apr;5(2):229-36. doi: 10.4161/mabs.23452. Epub 2013 Feb 13, supra).
Weekes et al. teaches methods for the treatment of hCMV infection in a subject (Abstract). Weekes et al. further teaches identification of hCMV proteins present at the cell surface of infected cells (Example 4). The viral protein UL141 was identified as a protein expressed on the plasma membrane of the infected cell (¶[0144], Fig. 17, Table 1), which can be used to target infected cells via therapeutics such as monoclonal antibodies (claim 1).
Weekes et al. further teaches methods of treating hCMV in a subject comprising administration of a monoclonal antibody (claim 5) that binds to a protein encoded by the genes disclosed in Table 1 (claim 1), which includes UL141. Weekes et al. teaches the isotype of the antibodies can be IgG, including IgG1 (¶[0077]).
Therefore, Weekes et al. teaches a method of treating hCMV in a subject comprising administration of a composition comprising at least one anti-UL141 monoclonal antibody (i.e., “an anti-viral composition”.
Weekes et al. does not teach antiviral compositions comprising at least one anti-UL141 antibody with a Fc mutation that increases immune cell binding function (i.e., the limitations of instant claim 1), or the elected Fc mutations of S239D (i.e., the limitations of instant claims 2-4)
Mimoto et al., in the same field of endeavor, teaches antibody engineering to increase the binding of a monoclonal antibody’s Fc region to FcγRs expressed on a variety of immune cells including NK cells (Introduction, ¶2). Mimoto et al. teaches the IgG1 Fc mutation comprising S239D, A3330L, and I332E amino acid substitutions increase binding of FcγIIIa by 255-fold when compared to a wild-type counterpart (Table 1); and increases ADCC levels when compared to a wild-type counterpart (Fig. 1).
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the instant application, to have modified the teachings of Weekes et al. in view of Mimoto et al. to generate anti-UL141 IgG monoclonal antibody compositions with the S239D, A330L, and I332E Fc point mutations (i.e., the limitations of instant claims 1-4) with a reasonable expectation of success, as Mimoto et al. teaches such engineering techniques (“Materials and Methods”). One would have been motivated to make this change for the purposes of increases ADCC levels of the antibody when used to treat hCMV infection in a subject.
Regarding claims 9, 14, 18, and 19, Weekes et al. teaches monoclonal IgG antibodies, which comprise a VH and a VL region, each of which contain 3 CDRs (i.e., “a plurality” of variable regions and CDRs) and are the gamma isotype, meeting the claim limitations.
Regarding claims 21 and 22, Weekes et al. further teaches pharmaceutical compositions comprising the anti-viral antibodies and an acceptable carrier (i.e., the limitations of instant claim 21; Weekes et al. ¶[0092]), as well as in combination with another antiviral such as ganciclovir (i.e., the limitations of instant claim 22; Weekes et al. ¶[0093], claims 27 and 28).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim 1, 5, 9, 14, and 18, 21, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Weekes et al. (supra) in view of Shields et al. (J Biol Chem. 2002 Jul 26;277(30):26733-40. doi: 10.1074/jbc.M202069200. Epub 2002 May 1).
Weekes et al. teaches methods for the treatment of hCMV infection in a subject (Abstract). Weekes et al. further teaches identification of hCMV proteins present at the cell surface of infected cells (Example 4). The viral protein UL141 was identified as a protein expressed on the plasma membrane of the infected cell (¶[0144], Fig. 17, Table 1), which can be used to target infected cells via therapeutics such as monoclonal antibodies (claim 1).
Weekes et al. further teaches methods of treating hCMV in a subject comprising administration of a monoclonal antibody (claim 5) that binds to a protein encoded by the genes disclosed in Table 1 (claim 1), which includes UL141. Weekes et al. teaches the isotype of the antibodies can be IgG, including IgG1 (¶[0077]).
Therefore, Weekes et al. teaches a method of treating hCMV in a subject comprising administration of a composition comprising at least one anti-UL141 monoclonal antibody (i.e., “an anti-viral composition”.
Weekes et al. does not teach antiviral compositions comprising at least one anti-UL141 antibody with a Fc mutation that increases immune cell binding function (i.e., the limitations of instant claim 1), or a nonfucosylated Fc region (i.e., the limitations of instant claim 5).
Shields et al., in the same field of endeavor, teaches modification of Asn297 of the Fc region of an IgG1 antibody to generate a nonfucosylated Fc region, which increased binding of FcγIIIa by 50-fold when compared to a wild-type counterpart (Abstract and Table 2); and increases ADCC levels when compared to a wild-type counterpart (Fig. 6).
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the instant application, to have modified the teachings of Weekes et al. in view of Shields et al. to generate a method of treating hCMV comprising administration of an anti-viral composition comprising an anti-UL141 IgG monoclonal antibody that is nonfucosylated with a reasonable expectation of success, as Shields et al. teaches such a modified IgG Fc region. One would have been motivated to make this change for the purposes of increases ADCC levels of the antibody.
Regarding claims 9, 14, 18, and 19, Weekes et al. teaches monoclonal IgG1 antibodies, which comprise a VH and a VL region, each of which contain 3 CDRs (i.e., “a plurality” of variable regions and CDRs) and are the gamma isotype, meeting the claim limitations.
Regarding claims 21 and 22, Weekes et al. further teaches pharmaceutical compositions comprising the anti-viral antibodies and an acceptable carrier (i.e., the limitations of instant claim 21; Weekes et al. ¶[0092]), as well as in combination with another antiviral such as ganciclovir (i.e., the limitations of instant claim 22; Weekes et al. ¶[0093], claims 27 and 28).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Weekes et al. (supra) in view of Mimoto et al. (supra), as applied to 1-4, 9, 14, 18, 21, and 22 above, and further in view of Wussow et al. (PLoSPath 2014 Nov 20;10(11):e1004524 doi: 10.1371/journal.ppat.1004524).
The combined teachings of Weekes et al. in view of Mimoto et al. have been discussed supra. The combined teachings do not teach vaccines comprising the monoclonal antibodies (i.e., the limitations of instant claim 20).
Wussow et al., in the same field of endeavor, teaches a hCMV vaccine (Abstract). Wussow et al. teaches the gH/gL-PC subunits derived from hCMV were used in a vaccine wherein an expression construct comprising a nucleic acid encoding the gH/gL-PC were injected into a mouse model of hCMV infection (pg. e1004524): “[v]accination of mice using MVA recombinants was performed…”. The gH/gL-PC vaccine successfully elicited an immunogenic response (Fig. 5), and successfully blocked hCMV infection of fibroblasts (Fig. 5, Results): “[c]o-expressed gH/gL-PC subunits induce NAb that prevent HCMV infection of fibroblasts”.
It would have been obvious to one with ordinary skill in the art, before the effective filing date, to have combined the anti-hCMV antiviral therapeutic of Weekes et al. in view of Mimoto et al. with the anti-hCMV antiviral vaccine of Wussow et al. (i.e., the limitations of instant claim 20) with a reasonable expectation of success, as the references teach anti-hCMV therapeutics that one with ordinary skill in the art would appreciate could be combined into a single therapy or composition for therapy. One would have been motivated to make this change for the purposes of treating hCMV in a patient via two routes – treating infected cells with the anti-UL141 monoclonal antibody of Weekes et al. in view of Mimoto et al., and vaccinating against further infection with the vaccine of Wussow et al. Additionally, it is prima facie obvious to combine two compositions each of which is taught by prior art to be useful for same purpose in order to form third composition that is to be used for very same purpose; the idea of combining them flows logically from their having been individually taught in prior art. In re Kerkhoven, 205 USPQ 1069, CCPA 1980. See MPEP 2144.06. In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Weekes et al. (supra) in view of Shields et al. (supra), as applied to 1, 5, 9, 14, and 18, 21, and 22 above, and further in view of Wussow et al. (supra).
The combined teachings of Weekes et al. in view of Mimoto et al. have been discussed supra. The combined teachings do not teach vaccines comprising the monoclonal antibodies (i.e., the limitations of instant claim 20).
The invention encompassed by the instant claims is a prima facie obvious variant of the combined teachings of Weekes et al. in view of Shields et al., and further in view of Wussow et al. for the same reasons discussed in the 35 U.S.C. § 103 rejection of Weekes et al. in view of Mimoto et al., and further in view of Wussow et al. supra.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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