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 Claims
Claims 1-16 are currently pending.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Applicant cannot rely upon the certified copy of the foreign priority application to overcome prior art rejections having an intervening critical date (i.e. between the PCT filing date of 7/30/201 and filing date of either of the foreign priority documents) because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d), a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Claim Objections
Applicant is advised that should claim 11 be found allowable, claim 13 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). In the instant case “obtained by freeze drying” as recited in claim 11 indicates a product-by-process limitation wherein the only structural limitations implied by the recited limitation are the limitations of the composition recited in claim 1. See MPEP 2113. Claim 13 recites a lyophilized formulation “being able to form the pharmaceutical composition according to claim 1 after reconstitution.” Again, the only structural limitations of the lyophilized formulation presented in the aforementioned description are the limitations of the composition recited in claim 1. Therefore, the limitations of claims 11 and 13 given patentable weight are the same: a lyophilized formulation comprising an anti-PD-1 and having the limitations of the composition recited in claim 1.
Claim Interpretation
Claim 12 recites product-by-process limitations “reconstituted” and “obtained by reconstituting the lyophilized formulation according to claim 11.” The structural limitations, “solution comprising an anti-PD-1” are only altered by the process in so far as they are required to contain the elements of the pharmaceutical composition recited in claim 1. See MPEP 2113. The process of reconstituting a lyophilized formulation does not distinguish the claimed invention from art teaching a solution comprising anti-PD-1 antibody and a buffer at a pH of about 4.7 to about 5.7.
In claim 1, “histidine-acetate” is listed as a species within the genus of “histidine salt buffers.” “Histidine-acetate” is interpreted to additionally be a species of the genus “acetate buffer” because it contains acetate. Thus a prior art reference teaching “histidine-acetate” reads on both “acetate buffer” and “histidine salt buffer.”
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-8 and 10-16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1-8, the phrases "preferably", “more preferably”, and/or “most preferably” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. “If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim.” See MPEP § 2173.05(d); emphasis added. The use of “preferably” is interpreted as exemplary language. In the instant case, it would have been unclear to a person of ordinary skill in the art whether the use of “preferably” indicates an optional embodiment or a required limitation, rendering the metes and bounds of the claims indefinite.
For the purposes of applying art, each limitation following "preferably", “more preferably”, and/or “most preferably” are interpreted as optional embodiments.
Claims 10-16 are rejected by virtue of their dependency on claim 1.
Specific claim locations reciting "preferably", “more preferably”, and/or “most preferably”:
Claim 1
Lines 4, 5, 6, 7, and 12
Claim 2
Lines 2 and 3
Claim 3
Line 2 and 3
Claim 4
Lines 2, 3, and 4
Claim 5
Lines 2, 3, 5, 6, and 7
Claim 6
Line 5
Claim 7
Line 8
Claim 8
Lines 10 and 16
In lines 7-8 of claim 1 there is no coordinating conjunction or other phrase (e.g. “wherein”) indicating the relationship between the limitations directed to the anti-PD-1 antibody’s CDRs and the rest of the claimed subject matter. In other words, some skilled artisan would argue that both the limitations directed to “the buffer is an acetate, a histidine….” And “the anti-PD-1 antibody comprises a heavy chain variable…” are required. Other skilled artisans would argue that the format of the claim indicates the buffer embodiments and anti-PD-1 antibody sequence embodiments are part of a list of alternative embodiments. Note well, semicolons may be used to join independent clauses without using a coordinating conjunction or list item lines that include multiple embodiments separated by commas. Thus, it would be unclear to the skilled artisan whether the anti-PD-1 antibody optionally has the recited CDR limitations in lines 8-16 or whether the limitations of lines 8-16 are a required.
To advance prosecution on the merits, claim 1 is interpreted with the scope of optionally comprising the anti-PD-1 antibody sequence recited in lines 8 and 16.
Claims 2-5, 8, and 10-16 are indefinite by virtue of their dependency.
In lines 13-16 of claim 1 the anti-PD-1 antibody comprises “an” HCDR1-3 and LCDR1-3 set forth in SEQ ID NO: X. Lines 11-12 recites “an LCDR2 set forth in SEQ ID NO: 12.” Each of the aforementioned SEQ ID NOs is a specific sequence with no variable residues. The scope of “an” HCDR or LCDR as set forth in each respective SEQ ID NO would be unclear to the person of ordinary skill because some skilled artisan would interpret “an” HCDR or LCDR set forth in said SEQ ID NO as including fragments of the sequence. However, other skilled artisans would interpret “an” HCDR or LCDR set forth in said SEQ ID NO as requiring all recited amino acids in each sequence.
Additionally, the variable residues of SEQ ID NOs: 65, 67 and 69 have multiple annotations in the sequence listing. For example, SEQ ID NO: 65 is annotated with both “Xaa is selected from the group consisting of Ile and Met” as well as “Xaa can be any naturally occurring amino acid.” Given that there are multiple interpretations for each variable residue, the person of ordinary skill would not be able to determine the metes and bounds of the claimed anti-PD-1 antibody comprising SEQ ID NOs: 65, 67, and 69.
Thus, the metes and bounds of the anti-PD-1 antibody as claimed are indefinite.
The scope of the recited anti-PD-1 antibody is interpreted as requiring all recited amino acids in each sequence, e.g. “comprises a [CDR] comprising SEQ ID NO: [X]”. Each variable residue is interpreted as any naturally occurring proteinogenic amino acid.
Claims 2-8 and 10-16 are rejected by virtue of their dependency on claim 1.
In claim 4, line 3 there is no coordinating conjunction or other phrase (e.g. “wherein”) indicating the relationship between the limitations directed to the surfactant concentration and the rest of the claimed subject matter. Thus, it would be unclear to the skilled artisan whether the surfactant optionally has the recited concentrations in lines 3-5 or whether the limitations of lines 3-5 are a required.
In claim 5, line 5 there is no coordinating conjunction or other phrase (e.g. “wherein”) indicating the relationship between the limitations directed to the osmotic pressure regulator concentration and the rest of the claimed subject matter. Thus, it would be unclear to the skilled artisan whether the osmotic pressure regulator optionally has the recited concentrations in lines 5-7 or whether the limitations of lines 5-7 are a required.
In claims 6 and 7 the anti-PD-1 antibody comprises “a” heavy and light chain variable region / constant region / full chain, respectively, “set forth in” SEQ ID NO: X. The scope of “a” heavy and light chain variable region / constant region / full chain “set forth in” each respective SEQ ID NO would be unclear to the person of ordinary skill because some skilled artisan would interpret “a” heavy and light chain variable region / constant region / full chain “set forth in” said SEQ ID NO as including fragments of the sequence. However, other skilled artisan would interpret “a” heavy and light chain variable region / constant region / full chain “set forth in” said SEQ ID NO as requiring all recited amino acids in each sequence. Thus, the metes and bounds of the CDRs of the claimed anti-PD-1 antibody are indefinite.
The scope of the recited anti-PD-1 antibody is interpreted as requiring all recited amino acids in each sequence, e.g. “comprises a [heavy and light chain variable region / constant region / full chain] comprising SEQ ID NO: [X]”.
Claim 16 recites the tumor is selected from “systemic light chain amyloidosis.” However, “systemic light chain amyloidosis” is not a tumor, but rather a condition that may or may not be associated with a tumor such as myeloma. The person having ordinary skill in the art would be unclear about the metes and bounds about claim 16 with respect to the scope of a “systemic light chain amyloidosis” tumor. Some skilled artisan would interpret this limitation of claim 16 as being limited to tumors that result in systemic light chain amyloidosis, but other skilled artisan would argue that the condition of systemic light chain amyloidosis broadens the scope of claim 15 to encompass treating all subjects having systemic light chain amyloidosis, including those without a tumor.
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 1-8 and 10-16 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 first embodiment of the anti-PD-1 antibody recited in claim 1 comprises the CDR sequences displayed in the table below.
CDR
SEQ ID NO:
Amino acid sequence
HCDR1
65
DYEXH
HCDR2
66
LXDPETGGXVYNQKFKX
HCDR3
67
EXXXXYXXXXDWYFDV
LCDR1
68
RSSQSXVHSXXXTYLE
LCDR2
12
KVSNRFS
LCDR3
69
FQGSHVPYX
Claim 1 does not specify the residues which “X” represents, although Table 1 on pg. 3 of the specification and the sequence listing sets forth an alternative embodiments with limited number of optional amino acid residues. That said, it is improper to read limitations from the specification into the claims. MPEP 2111.01. Portions of the specification describing embodiments wherein each variable residue are limited to particular amino acids do not constitute clear lexicography or disavowal. Therefore, the skilled artisan would have reasonably interpreted the variable residues of the CDRs, under the broadest reasonable interpretation, as any proteinogenic amino acid residue. Provided this BRI, the breadth of the claimed anti-PD-1 antibody according to the aforementioned CDR sequences encompasses 2017 different species, which is approximately 7 orders of magnitude larger than the estimated number of stars in the Milky Way (NASA retrieved November 3, 2025 from the Internet at <URL: https://universe.nasa.gov/stars/basics/>).
Claim 6 describes anti-PD-1 antibodies of claim 1 having at least 90% sequence identity to SEQ ID NO: 27 (VH) and 55 (VL). Given the scope encompasses each sequence alteration occurring the CDR, claim 6 does not further limit the scope of the CDRs of the anti-PD-1 antibodies described in claim 1. For example, 90% sequence identity to the VH having 125 residues allows for 12 amino acids to be altered. HCDR1-3 combined as described by claim 1 have 10 variable residues. Thus, the VH according to claim 6 permits all 10 variable residues set forth in claim 1 to differ.
Similarly, claim 7 does not further narrow the scope of the CDRs of the anti-PD-1 antibodies according to claim 1. For example, a sequence having 85% identity to SEQ ID NO: 74, a heavy chain sequence having 452 residues, encompasses up to 67 alterations in the amino acid sequence.
MPEP § 2163 states:
"The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice ... reduction to drawings ... or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. In unpredictable arts a widely variant genus cannot be represented by only one species. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A ‘representative number of species’ means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. Furthermore, establishment of a ‘reasonable structure-function correlation’ can also describe a genus and may be established ‘by the inventor as described in the specification,’ or ‘known in the art at the time of the filling date.’ See MPEP 2163 (II)(A)(3)(a)(ii) and Abb Vie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that ‘only describe[d] one type of structurally similar antibodies’ that ‘are not representative of the full variety or scope of the genus.’)."
Starting at ¶ 148 on pg. 45 of the specification, Applicants immunized mice with recombinant human PD-1 protein, isolated antibody producing cells to form hybridomas, and subsequent screening and selection. Alternatively, the sequences of antibodies produced upon immunization are obtained to generate a phage display library which is subject to screening (see specification starting at ¶ 149 on pg. 47). Applicant obtained a “plurality of antibodies with good activity” (see ¶ 155 on pg. 50), and sets forth the sequences of three clones: M23, M32, and M33 (pg. 50 through pg. 52). M23 and M32 and derivatives thereof pertain to antibodies within the scope of claim 1.
In Example 2, Applicant generated humanized antibodies clones M23 and M32 amounting to 20 additional species. M23 humanization resulted in 8 antibodies, Hu23-1 through Hu23-8, comprising 4 unique VH sequence combined with 2 unique VL sequences (pgs. 53-55), and M32 humanization resulted in 12 antibodies, Hu32-1 through Hu23-12, comprising 6 unique VH sequences combined with 2 unique VL sequences (pgs. 56-58).
Hu23 LCDR1 was further subject to site-directed mutagenesis, expanding the number of Hu23 variants to include Hu23-9 through Hu23-56, or 48 additional species wherein 6 retained the ability to bind to PD-1 (§ 4 of Example 2 on pgs. 62-65).
Finally, combinations of Hu32 variable regions with Hu23 variable regions were made because their parent clones, M32 and M23 respectively, had high sequence identity. The CDRs of the instant claims define residues that were shared between Hu32 and Hu23, however the variable residues of the instant claims encompass more variation than that described by the general formulas of variable region consensus sequences in Table 13. Ultimately, the combinations of Hu32 and Hu23 variable domain resulted in 84 (Table 14) + 6 (Table 15) = 90 additional species.
Screening of the generated antibodies demonstrated that of the 20+48+90 = 158 antibody structures developed from M23 and M32, 20 retained binding to PD-1 (see ¶ 230 on pg. 70 and Table 16 spanning pg. 70 through 72).
However, 20 antibodies within the scope of claim 1 that have the claimed property of binding PD-1 is a very small fraction of the antibodies described in claim 1 and is not representative of the full scope of the variation present in this claimed genus. Thus, one of ordinary skill in the art would not be able to reasonably say that the Applicant possessed a representative number of species that reflects the variation of the claimed genus.
The factual inquiry now turns upon whether there is a correlation between structural and functional characteristics. Applicant shows that only 20 of 158 structure generated have PD-1 binding properties. Thus, the structure recited in instant claim 1 is insufficient to account for the property of binding to PD-1.
"A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) (Claims directed to PTFE dental floss with a friction-enhancing coating were not supported by a disclosure of a microcrystalline wax coating where there was no evidence in the disclosure or anywhere else in the record showing applicant conveyed that any other coating was suitable for a PTFE dental floss.)
The art is highly unpredictable in respect to correlations between the structure and binding properties of CDRs.
Rudikoff et al. found that a single amino acid change in a CDR completely altered antigen-binding specificity (Rudikoff et al. Proc Natl Acad Sci 1982. 79: 1979-1983; cited herewith, pg. 1982, left column, second full paragraph). Bedouelle et al. (FEES J. 2006 Jan;273(1):34-46; cited herewith) examined the effects of alanine substitutions on each of the residues of the antibody heavy and light chain CDR3 regions and showed mutation of certain residues cause a > 100 fold drop in the “off rate” for ligand dissociation (Bedouelle et al., pg. 38-39; see Table 2). Bedouelle suggests that some mutations had a direct effect on antigen binding while others indirectly affect the conformation of the antigen binding site, thereby indirectly affecting antigen binding (see Discussion Section). This illustrates the unpredictability of making mutations within the CDRs of an antibody, especially the CDR3 domains. Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28; cited herewith) teaches that antigen binding is resultant from the 6 CDRs, or hypervariable regions, the variable region of an antibody (see, page 416, column bridging paragraph, emphasis added). Vajdos used a shotgun scanning mutagenesis using phage displayed libraries of protein mutants, which required extensive experimentation to comprehensively scan the potential CDR sequence space (see page 416, right column, 2nd paragraph and pages 425-427, Materials and Methods). Furthermore, even after performing this comprehensive scanning mutagenesis of all CDR residues from the particular anti-ErB2 antibody, Vajdos would still not have been able to say which CDR residues were actually involved in antigen binding, and which were involved in stabilizing the secondary and tertiary structure of the CDRs within the context of the heavy and light chains as a whole, without the structure of the unbound antigen-binding site of the antibody to aid in their analysis (see, in particular, Discussion, pages 422- 425). Rather, Vajdos needed to perform not only a comprehensive shotgun scanning mutagenesis of all CDR residues of the antibody under study, but also needed a structure of the unbound antigen binding site in hand to gain a sufficient understanding of the contribution of each CDR to antigen-binding to adequately predict which CDR residues can be changed, and to what extent, or in what context of additional compensatory mutations in other regions of the antibody.
Collectively, Rudikoff et al. Bedouelle et al., and Vajdos et al. demonstrate the amino acids of a CDR that are responsible for binding with a particular antigen cannot be determined by observation of the amino acid sequence alone. Indeed, Vajdos et al. showed it required the epitope of the antigen as well. Additionally, the ability to bind to a particular antigen is extremely sensitive to changes in CDR sequences.
In conclusion, there are no representative species in the art and the species disclosed in the specification are not sufficient to represent the full breadth of the claimed invention according to instant claims 1, 6 and 7. Furthermore, a structure-function correlation is not shown in the specification or the art to account for the high degree of variability of the CDRs as laid forth in the instant claims. While the Applicant has reduced to practice a portion of the scope of the instantly claimed genus, there is not a sufficient written description of the antibodies according to instant claims 1, 6 and 7. Thus claims 1, 6 and 7 are rejected under of 35 U.S.C. 112(a) for failing to comply with the written description requirement. Claims 2-5, 8, and 10-16 are additionally rejected by virtue of their dependency on claim 1.
Note well, even if Applicant were to amend claim 1 to limit the variable residues to the amino acids recited in Table 1, the genus of claimed antibodies would still encompass 4.9 x 105 individual antibodies. Applicant is cautioned that doing so may not sufficiently limit the scope of the claimed genus to overcome the written description rejection.
Claims 1-8 and 10-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
As stated in MPEP §2164.01 (a), "there are many factors to consider when determining
whether there is sufficient evidence to support a determination that a disclosure does not satisfy
the enablement requirement and whether any experimentation is 'undue'." These factors include,
but are not limited to:
1. The breadth of the claims;
2. The nature of the invention;
3. The state of the prior art;
4. The level of skill in the art;
5. The level of predictability in the art;
6. The amount of direction provided by the inventor;
7. The presence or absence of working examples;
8. The quantity of experimentation necessary to make or use the invention based on the
disclosure.
See In re Wands USPQ 2d 1400 (CAFC 1988).
Regarding the breadth and nature of the invention, please see pgs. 8-9 of this Office Action above for a description of the breadth and nature of the anti-PD-1 antibodies.
The amount of guidance or direction needed to enable the invention is inversely related to
the amount of knowledge in the state of the art as well as the predictability in the art. In re
Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The state of art indicates that antigen specificity is extremely sensitive to changes in as little as one amino acid in a CDR (see discussion on Rudikoff et al., Bedouelle et al., and Vajdos above). The does not provide directions on how to make and use the invention of an antibodies that bind to PD-1 with CDRs as set forth in instant claim 1. Moreover, making changes to the binding region has been shown to yield highly unpredictable results in terms of binding specificity. Vajdos et al. teaches that an antibody moiety’s essential structural components for binding to a cognate antigen cannot be derived from the observation of the antibody’s binding region (i.e. VH, VL, and/or CDRs) alone, the cognate antigen must also be present. This would turn the process of determining which combinations of CDRs recited in claim 1 have the property of binding to PD-1 toward blindly testing each species within the recited genus. Since the claims encompass as 2017 structures set forth in instant claim 1, an undue amount of experimentation would be need to make the anti-PD-1 antibodies as claimed. For example, each individual structural species would need to be assessed for its ability to bind to PD-1. The specification does not point the skilled artisan to what structural properties of said 2017 would result in the property of binding to PD-1. Indeed, of the 158 structures that applicants reduced to practice, only 20 actually possessed the property of binding PD-1.
“As long as the specification discloses at least one method for making and using the
claimed invention that bears a reasonable correlation to the entire scope of the claim, then the
enablement requirement of 35 U.S.C. 112 is satisfied. In re Fisher, 427 F.2d 833, 839, 166
USPQ 18, 24 (CCPA 1970)” (see MPEP 2164.01(b)).
Specification pgs. 45-48 describes conventional methods well known in the art that were employed to generate the antibody species disclosed. As is evidenced by what is known in the art, there is no way to know which amino acid changes would result in improved binding affinity, thus the specification does not provide directions for more than rote trial and error experimentation. Therefore, the specification does not provide sufficient instruction to make the full breadth of the anti-PD-1 antibodies beyond trial and error experimentation. The generation of 20 antibodies out of 158 structures does not bear a reasonable correlation to the entire scope of the claimed invention which encompasses innumerable variations of the antigen binding domain described as having 2017 structures as set forth in instant claim 1.
MPEP 2164.01 states:
“[t]he standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Minerals Separation Ltd. v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term "undue experimentation," it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).”
Application of the Wands factors as discussed reveals that there is not enough support in the specification or the art to make the full scope of the anti-PD-1 antibodies without an unreasonable amount of experimentation because of the unpredictable and laborious process of identifying which CDRs result in the claimed function of binding to anti-PD-1. Therefore, upon contemplation of In re Fisher and the Wands factors, claims 1-8 and 10-16 have been found to lack enablement.
Claims 15-16 is 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 for therapeutically treating cancer, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an anti-PD-1 antibody having HCDR1-3 set forth in SEQ ID NOs: 8-10 and a LCDR1-3 set forth in SEQ ID NOs: 49, 12, and 13, does not reasonably provide enablement for a method for treating (i.e. including preventive or prophylactic measures) or preventing a disease or disorder comprising administering to a subject the antibody of claim 1 wherein the disease or disorder is a tumor. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Claims are given their plain and ordinary meaning as would be reasonable to one of ordinary skill in the art, unless applicant acts a lexicographer by clearly setting forth a definition in the specification (see MPEP 2111). The term “tumor” to one of ordinary skill in the art encompasses both benign growths as well as malignancies. Thus, in the absence of a definition provided by the instant specification, claims 15-16 are interpreted as encompassing administering an anti-PD-1 antibody for the purpose of treating or preventing both benign and cancerous tumors. In ¶ [0122] of the instant specification, “treating” has been redefined to mean “therapeutic treatment, preventive or prophylactic measures, and research and diagnostic applications.” The scope of “treating or preventing” a tumor requires the skilled artisan to identify which subjects will develop a tumor.
“A specification may call for a reasonable amount of experimentation to make and use a patented invention. What is reasonable in any case will depend on the nature of the invention and the underlying art. Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023) (citing Minerals Separation Ltd. v. Hyde, 242 U.S. 261, 270-71 (1916)).” (MPEP 2164.01). In the instant case, the nature of preventing cancer with an anti-PD-1 antibody in subjects who may acquire cancer requires the ability to anticipate which subjects will ultimately develop cancer.
Cancer is a highly heterogenous disease and no one person’s cancer is the same as another’s. The etiology of each cancer is complicated and poorly understood, and as a consequence the skilled artisan is generally unable to say in advance who will eventually develop cancer. Many potential factors have been hypothesized to cause a person to be at risk of, e.g., a brain tumor, only to be shown to have no predictive value in subsequent work (see, e.g., McKinney. J Neurol Neurosurg Psychiatry. 2004. 75(Suppl II):ii12–ii17, at pages ii15-16, cited herewith).
Hippisley-Cox and Coupland developed algorithms for predicting the risk of developing future cancer over a 10-year period with 11 different types of cancer using data on risk factors reported in patient’s electronic records (Hippisley-Cox and Coupland. 2015. BMJ Open. 5:e007825, cited herewith; see Introduction on pg. 2). Risk factors included general factors such as BMI, smoking status, alcohol use, as well as cancer-type specific factors including family history (pg. 3, left col). Even in the top 10% of women at the highest risk of cancer, the best performing algorithm, which compared to the literature had a “very good” performance, only had a sensitivity of 67% (Abstract, pg. 15, left col., and pg. 21, left col.).
Presently, pembrolizumab, the first anti-PD-1 treatments approved by the FDA, is indicated for unresectable, metastatic, recurrent, or advanced cancers (Keytruda® FDA Label. June, 2018. Retrieved from the Internet on November 7, 2025 from <URL: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125514s030lbl.pdf>). With respect to the use of immune checkpoint inhibitors in preventive medicine, Chen et al. found in a sample size of 10 mice that anti-PD-1 treatment of precancerous oral lesions delayed and/or reduced the number of tumors (Oncoimmunol. 2018. 7(2):e1388484, cited herewith; pg. 3-5 and Fig. 4), however, it studied a limited population and did not prevent malignancy from occurring. Thus, the art with respect to using PD-1 inhibitors to reverse the course of developing cancer is in its nascent stages of investigation.
While cancer prediction and prevention have been a long-sought after goal, the aforementioned art indicates a high level of unpredictability with respect to identifying whether an individual will develop cancer. Moreover, the use of immune checkpoint blockade in prevention of cancer, let alone diseases in general, is underdeveloped.
Additionally, there is no art on therapeutic or preventive application of anti-PD-1 antibodies to benign tumors.
As long as the specification discloses at least one method for making and using the claimed invention that bears a reasonable correlation to the entire scope of the claim, then the enablement requirement of 35 U.S.C. 112 is satisfied. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). (MPEP 2164.01(b)).
In Example 4, Applicant shows that anti-PD-1 antibodies induce IFNy secretion from cells in PBMC-T lymphocyte activation. In Example 5, administering anti-PD-1 reduced tumor burden in a murine colon cancer model. However, there are no working examples showing anti-PD-1 preventing cancer, there is no direction on how to predict what subjects will develop a tumor, and there is no direction or examples showing therapeutic or preventive activity against benign tumors.
Thus, the instant specification fails to remedy the deficiencies in the art with respect to predicting which subject would acquire cancer and the efficacy of anti-PD in stopping cancer from ever developing. Rather, given the nature of the invention and underdevelopment of the art, one of ordinary skill would have to practice undue experimentation to practice the scope of preventing cancer with an anti-PD-1 antibody.
In turning to experimentation to determine which benign tumors could be treated or prevented or which cancers could be prevented with anti-PD-1, the skilled artisan would have to practice the full translation spectrum of research (i.e. basic mechanistic research, pre-clinical animals, and clinical trials) for a vast number of diseases. "‘The test [for undue experimentation] is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed.’" In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) (citing In re Angstadt, 537 F.2d 498, 502-04, 190 USPQ 214, 217-19 (CCPA 1976)). Clearly, this would go beyond what is considered routine experimentation in the art. Indeed, although the ordinarily skilled artisan is presumed to be highly skilled in the art, the quantity of experimentation that is not routine needed to determine which benign tumors could be treated or prevented or which cancers could be prevented with anti-PD-1 would impose an undue burden given the lack of guidance in the specification for using the invention commensurate in scope with the instant claims. Thus, the person of ordinary skill would have to practice undue experimentation to determine the full scope claims 15 and 16. Indeed, the guidance in the art does not extend beyond the use of anti-PD-1 to therapeutically treat patients with cancer, and the specification provides insubstantial direction on how to use the anti-PD-1 commensurate in scope with claims 15 and 16.
“Tossing out the mere germ of an idea does not constitute enabling disclosure. While every aspect of a generic claim certainly need not have been carried out by an inventor, or exemplified in the specification, reasonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Genentech Inc. v. Novo Nordisk A/S, 42 USPQ2d 1001, 1005 (CA FC 1997).
“A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” (MPEP 2164.01(a)).
Thus, in view of the foregoing Wands analysis, claims 15 and 16 are rejected on the grounds that one of ordinary skill in the art would not be able to practice the full scope of treating (i.e. treating and/or preventing) an immune disorder or cancer in a subject administered the antibody of instant claim. The scope of enabled matter recited in the claim is restricted to therapeutically treating cancer in a subject comprising administering to the subject an effective amount of a pharmaceutical composition comprising an anti-PD-1 antibody having HCDR1-3 set forth in SEQ ID NOs: 8-10 and a LCDR1-3 set forth in SEQ ID NOs: 49, 12, and 13.
Note well, in ¶ [0122] of the instant specification, “treating” has been redefined to mean “therapeutic treatment, preventive or prophylactic measures, and research and diagnostic applications.” Therefore, merely canceling the term “preventing” from claim 15 is not sufficient to overcome the scope of enablement rejection in so far as a skilled artisan would still have to be able to identify which subjects develop a tumor to practice the claimed invention.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-5, 10, and 13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dai in WO 2018/183459 published October 4, 2018.
In ¶ [0622] on pg. 345 spanning pg. 346, Dai discloses that the final step of purifying the anti-PD-1 antibodies is buffer exchange in a stock solution of 10 mM succinate, 9% sucrose, 0.05% PS20, at a pH of 5.5 and an anti-PD-1 concentration of 20 mg/mL, as in instant claims 1, 2, 3, 4, 5, 10, and 13.
Claims 1-5, 8, and 11-16 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Zhou in WO 2019/206281 A1 published on October 31, 2019 (citation from English translation attached).
Zhou teaches a formulation comprising 20-30 mg/mL of anti-PD-1 antibody, 80 mg/mL of sucrose, 10 mM histidine-acetate buffer, 0.4 mg/mL of polysorbate 20, wherein the pH is 4.5-5.5 (see Item 17 on pg. 5 and Item 16(4)), anticipating instant claims 1-5, 8, and 12. Note well, claim 12 is anticipated because the structural limitations of the claim (i.e. a solution comprising an anti-PD-1 composition) are met by Zhou. See Claim Interpretation above and MPEP 2113. Instant claim 11, 13, and 14 are anticipated at Zhou pg. 4 in lines 7-11. (“The solution formulation... is also compatible with glass and stainless steel containers …a lyophilized preparation obtained by lyophilization of the above [i.e. including 80 mg/mL of sucrose, 10 mM histidine-acetate buffer, 0.4 mg/mL of polysorbate 20, wherein the pH is 4.5-5.5]”). At pg. 4 in lines 38-39, Zhou teaches the anti-PD-1 solution is used to treat head and neck cancer, anticipating instant claims 15-16.
Claims 1, 6, 7, and 12 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Gu in WO 2020/156509 A1 published August 6, 2020 (citations from US 2022/0098304 A1 deemed an English translation).
On pg. 15 in ¶ [0178], Gu teaches that anti-PD-1 antibodies are purified by eluting a column with acetic acid/sodium acetate and adjusting the pH to 5-6, anticipating instant claims 1 and 12. Note well, claim 12 is anticipated because the structural limitations of the claim (i.e. a solution comprising an anti-PD-1 composition) are met by Gu. See Claim Interpretation above and MPEP 2113. Gu also teaches an anti-PD-1 antibody, Hu23-11, having Hu23VH1 and Hu23VL1(N28T) (Table 12 on pg. 21; pg. 20 SEQ ID NO: 55; pg. 17 SEQ ID NO: 27). Hu23-11 was formatted as an IgG4 antibody and shown to have PD-1 binding properties (pg. 24, Table 16, SEQ ID NO: 74; pg. 25, SEQ ID NO: 75). Hu23-11 teaches the limitations of the anti-PD-1 antibody according to instant claims 6 and 7.
The applied reference has a common assignee (Shanghai Hengrui Pharmaceutical Co., Ltd.) with the instant application. Note well, the second assignee, Jiangsu Hengrui Medicine Co. Ltd. has a different name than the assignee Jiangsu Hengrui Pharmaceutical Co. Ltd. listed in the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Applicant cannot rely upon the certified copy of the foreign priority application to overcome this rejection under 102(a)(1) because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
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 1-9 and 11-16 are rejected under 35 U.S.C. 103 as being unpatentable over Gu in WO 2020/156509 A1 published August 6, 2020 (citations from US 2022/0098304 A1 deemed an English translation); as applied to claims 1, 6, 7, and 12 above and further in view of Sharma in WO 2018/204368 published November 8, 2018.
In claim 12, Gu teaches a pharmaceutical composition comprising an anti-PD-1 antibody having the CDRs of the instantly claimed anti-PD-1 antibody. In ¶’s [0149]-0150], Gu teaches that pharmaceutical compositions comprise a carrier, including buffer, and sugars / polyols.
While Gu teaches a pharmaceutical compositions comprising the instant claimed anti-PD-1, Gu does not teach that the composition comprises 10 mM acetic acid-sodium acetate buffer at a pH of 5.2, an anti-PD-1 antibody concentration of 120 mg/mL, 80 mg/mL of sucrose, and 0.6 mg/mL of polysorbate 80.
However, Sharma’s claim 3 recites an anti-PD-1 antibody formulation comprising about 5 to 200 mg/mL of anti-PD-1, about 5 mM to about 20 mM buffer, a stabilizer of about 6% to about 8% (w/v) sucrose, and about 0.01 to 0.10% non-ionic surfactant, wherein the formulation has a pH between 5.0 and 6.0, as in instant claims 1, 2, 3, 4, and 5. In claim 2, Sharma teaches that the buffer is acetate, and on pg. 28 in lines 9-16 Sharma discloses sodium acetate. Sharma discloses on pg. 30 in lines 5-6 that the preferred surfactant is polysorbate-80. In claim 27 of Sharma, the anti-PD-1 antibody formulation is liquid, as in instant claim 12. In claim 28 of Sharma, the anti-PD-1 antibody formulation is lyophilized, as in instant claims 11 and 13. In claim 30 of Sharma the formulation is contained in a glass vial, as in instant claim 14. In claim 41 of Sharma the anti-PD-1 antibody is administered to a patient to treat head and neck cancer, as in instant claims 15 and 16.
It would have been prima facie obvious to combine the composition of Sharma with the anti-PD-1 antibody of Gu. The skilled artisan would have been motivated by the explicit and implicit teachings of Sharma regarding the use of the compositions with a generic anti-PD-1 antibody. The skilled artisan would have been motivated to select Gu’s anti-PD-1 because of the experimental evidence that said anti-PD-1 is effective for treating cancer. Indeed, even if the skilled artisan were to start with the teachings of Gu, one would have had the motivation to formulate and store the anti-PD-1 with pharmaceutically acceptable excipients that are known in the art for anti-PD-1 antibodies, leading the skilled artisan toward the disclosure of Sharma.
MPEP 2144.05(II)(A) instructs that it is prima facie obvious to optimize concentrations of components. Routine Optimization - Optimization Within Prior Art Conditions or Through Routine Experimentation:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)[.]
Additionally, as set forth in MPEP 2144.05(II)(B), there is a Motivation to Optimize Result-Effective Variables:
… In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because "obvious to try" is not a valid rationale for an obviousness finding. However, in KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421 ("The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103."). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a person of ordinary skill in the art to experiment to reach another workable product or process.
Regarding the limitations of claim 9, Sharma discloses a limited