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 .
DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of Group I, claims 16-34 and species: metastatic nasopharyngeal carcinoma, CCND1, toripalimab, antibody in combination with gemcitabine and cisplatin, a fixed dose of 240 mg, 1000 mg/m^2 body surface area, 80 mg/m^2 body surface area, and once every three weeks in the reply filed 12/15/2025 is acknowledged.
Claims 35-36 are withdrawn from consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions and species, there being no allowable generic or linking claims. Election was made in the reply filed 12/15/2025.
Priority
Applicant's claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/CN2021/114668 filed 08/26/2021.
Acknowledgment is made of applicant's claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in the instant application on 02/27/2023. Foreign priority is claimed through CN202010879644.8 filed on 08/27/2020, CN202110343389.X filed on 03/30/2021, and CN202010926736.1 filed on 08/12/2021. All claims have been given an effective filing date of 08/27/2020.
Claim Status
Claims 23-24 and 28 have been amended.
Claims 1-15 have been cancelled.
Claims 16-36 are pending.
Claims 35-36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions or species, there being no allowable generic or linking claim.
Claims 16-34 are pending and under consideration.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 02/12/2025, 11/18/2025, and 01/15/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 16-25 and 30-31 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.
Instant claims 16-25 recite a method of preventing or treating a malignant cancer comprising administering an anti-PD-1 antibody in combination with “gemcitabine-cisplatin”. The terminology “gemcitabine-cisplatin” is not defined in the instant specification. It is unclear if this terminology refers to a conjugate including both gemcitabine and cisplatin, or if the two separate drugs are to be administered separately or in conjunction with one another in a particular manner.
Instant claim 30 is indefinite over the use of the "e.g." phrase. This phrase renders the claims indefinite as it is not clear if the limitations are required or how the phrases after "e.g." alter the recited limitations. Therefore, the metes and bounds are unclear. See MPEP § 2173.05(d).
Instant claim 31 recites the term “optionally”. The phrase “optionally” is interpreted as "for example" which renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. For the purposes of examination, the instant claims will be interpreted without the optional limitations as they are not required or claimed as necessary to the invention. See MPEP § 2173.05(d).
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 16-34 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.
Claims 16-34 are directed to any antibody that binds PD-1 and a combination therapy comprising gemcitabine and cisplatin. As such, the claim is directed to an antibody defined entirely by function (binding). See MPEP §2163(I)(A) which states:
"The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art recognized correlation or relationship between the structure of the invention and its function. A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.”
In this case, antibodies generally share certain characteristics such as Fc regions or hinge regions. However, these structures are not correlated with the binding function of the antibody. The hyper variable regions (HVRs), i.e., complementarity determining regions (CDRs) of an antibody, are well established in the art as the portion of the binding region which imparts the specificity of an antibody. However, there is no way to a priori look at an antigen sequence (PD-1) and envisage the combination of six CDRs that will bind that antigen. First, even highly related CDRs may not bind the same target. See for example Kussie (instant PTO-892) who demonstrates that a single amino acid change in the heavy chain of an antibody which binds p-axophenylarsonate (Ars) completely abrogates the ability of the antibody to bind Ars but adds the functionality of binding the structurally related p-azophenylsulfonate (e.g., abstract). Second, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (p.7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on page 11).
Thus, the art recognizes that the CDRs define the binding properties of an antibody and that even single amino acid changes to this region can completely abrogate the binding specificity of an antibody. As a further example, see Chen et al., 1995 (instant PTO-892) which demonstrates single amino acid changes in the VH CDR2 sequence can increase binding, decrease binding, destroy binding, or have no effect on binding when compared to the wild-type antibody.
See also Koenig 2017 (instant PTO-892), which provides a large mutation analysis study where every amino acid in both variable regions are substituted with every other amino acid. Looking at figure 1 of Koenig, the bottom half of each section (labeled VEGF) relates to the ability of the mutant to bind the original target, with blue meaning a reduced affinity and black meaning a complete loss of binding ability. In VH-CDR2, for example, mutating any given residue to cysteine, which is encompassed by the instant claims, resulted in reduced binding at 12 residues and a complete loss of binding at 5 residues. That is, at 100% of the positions, mutation to cysteine reduced or ablated the antibody’s ability to bind the target. Looking at a specific position, in 100% of the mutations of residue 55, binding was reduced (15/19) or eliminated (4/19). While residues 56-65 appear more tolerant of change, residues 50-55 are generally intolerant of change.
It is appreciated that Koenig is studying one specific antibody and there is no evidence that the instant antibodies would react in the same way. However, this is part of the problem. It is entirely unclear from the specification which residues of Applicant’s CDRs are tolerant or intolerant to change, and whether those tolerant positions are only tolerant to conservative mutations. The fact that some residues might tolerate mutation does not convey to the skilled artisan that Applicant knew which of the claimed residues were tolerant of such, i.e., does not convey that Applicant was in possession of those sequences which are mutated yet preserve the claimed function. In other words, the specification fails to convey possession of an invention commensurate in scope with what is now claimed and therefore fails to meet the written description requirement. Looking at Koenig figure 2A, ~200 mutations in the CDR region of the VH chain completely abrogates any binding. While 2B appears to indicate that the CDRs of VL are more tolerant of change than the heavy chain CDRs, still over half of the mutations reduce binding compared to the parent.
Thus, making changes to the CDR sequence of an antibody is a highly unpredictable process and the skilled artisan could not a priori make any predictions regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required functions.
The specification discloses six antibodies: nivolumab, pembrolizumab, toripalimab, sintilimab, camrelizumab, tislelizumab, cemiplimab, and toripalimab. The specification also discloses the toripalimab antibody via its sequences with SEQ ID NOs: 1-6 as the heavy and light chain CDR sequences, SEQ ID NOs: 7-8 as the heavy and light chain variable region sequences, and SEQ ID NOs: 9-10 as the heavy and light chain sequences. However, as discussed above, without any way to determine how broad the genus of such antibodies are, there is no way to determine if these antibodies represent the full breadth of what is claimed in instant claims 16-21 and 26-33. Therefore, it appears that the instant specification does not adequately disclose the breadth of the anti-PD-1 antibodies recited in the instant claims. In light of this, a skilled artisan would reasonably conclude that Applicant was not in possession of the genus of all such anti-PD-1 antibodies at the time the instant application was filed. The disclosure of these specific antibodies would not convey to the artisan that Applicant was in possession of the full genus of all antibodies which possess the required functions nor does it allow the skilled artisan to envisage the specific structure of such antibodies.
Instant claims 22-25 and 34 recite the heavy and light chain CDRs, heavy and light chain variable region, and heavy and light chain sequences of the antibody that binds to PD-1 with the terminology “an amino acid set forth in”. There is no limitation or exclusion in the claim language that prevents the modifications from occurring within the CDR region due to the claim language of “an amino acid set forth in”, which widens the scope of the claim to encompass an immense number of unknown molecules that share some identity to the claimed sequences and can bind to the claimed receptor. Applicant has not demonstrated that they are in possession of all the molecules that fall within the immense scope of the claim that are able to achieve the claimed function.
The use of “an amino acid sequence set forth in” can be interpreted as comprising the whole sequence or only comprising some of the amino acids contained within the sequence. As currently recited, the language of “an amino acid sequence” reads on less than the amino acids listed in the sequence identity number that are capable of binding to any isolated antigen. The minimum requirement of any sequence that would meet the limitations of the claim as written only requires a few amino acids in common with the claimed sequence. There is a lack of support for all of the potential amino acid sequence as claimed that is capable of binding to any antigen as written. Applicant is encouraged to amend the claim language to “… regions comprising the amino acid sequence of SEQ ID NO: … ” in the instant claims to obviate this rejection.
Further note the decision in Amgen v. Sanofi 2017, where the Court supported previous decisions (Centocor 2011; Abbvie 2014) that defining an antibody solely by what it binds does not satisfy the written description requirement, stating that this would allow patentees to “claim antibodies by describing something that is not the invention, i.e., the antigen”. This decision has precipitated guidance to the Office instructing that the portion of MPEP 2163 regarding the “newly characterized antigen test” (indicating a well-characterized antigen is sufficient to satisfy written description for antibodies which bind that antigen) should no longer be used and that contrary materials should not be relied upon as reflecting the current state of the law.
It is appreciated that certain claims do include at least one CDR, e.g., claim 22 requires all six CDRs, but contains claim language which encompasses a broad variety of variants, a variant being defined as noted above to include no particular structure so long as the function is retained. Claims 16-21 and 26-33 leave all six CDRs wholly undefined.
However, as above, arbitrarily altering any amino acid in the CDR of an antibody is unpredictable and the specification does not convey possession of any CDRs other than those of the disclosed antibodies. Further, it is well-known in the art that specificity of an antibody stems from the interaction of six CDRs. Moreover, CDRs are not generally recognized as interchangeable, such that using one CDR from one antibody would not be reasonably expected to confer the same binding properties or even the same binding target when combined with two to five CDRs from other antibodies. For example, WO 2008068048 (instant PTO-892) discloses an antibody with a heavy chain comprising three CDRs (SEQ ID NO: 2) that binds secreted aspartyl protease from Candida sp. US 20170355756 (instant PTO-892) describes the same three CDRs in the heavy chain (C10-VH3) combined with a different light chain that binds human TDP-43. There is no evidence in the instant specification that a single CDR placed in the context of two to five other CDRS, regardless of what those other CDRs are, would result in the required function, nor that a single chain is correlated to the required function when combined with any other chain. As such, the specification fails to set forth a structure-function correlation sufficient to claim all possible antibodies defined by function.
As such, the disclosure of six antibodies does not convey possession of other antibodies with the same binding properties; possession of the precisely defined sequence of six CDRs is required.
With respect to claims 16-34, it is recognized that information which is well known in the art need not be described in detail in the specification (MPEP §2163(II)(A)(2)). See, e.g., Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1379-80, 231 USPQ 81, 90 (Fed. Cir. 1986). However, sufficient information must be provided to show that the inventor had possession of the invention as claimed. MPEP §2163(II)(A)(3)(a) also discusses Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004), where a method of using a PGHS-2 inhibitor did not meet the written description as the inhibitor itself was not sufficiently described, clearly indicating that written description of the compound is still required in a method of using that compound. In this case, it is clear from the specification that the invention is in a new antibody, or at the least disclosure of a new antibody that could not have been envisaged from the prior art indicates that the prior art was not in possession of all “PD-1 antibodies”. Thus, the prior art cannot provide sufficient written description of this genus of compounds and the specification as filed, disclosing one antibody, does not sufficiently describe the genus either as there is an unknown amount of structurally distinct antibodies in this genus (see Amgen and Centocor decisions discussed above).
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Vas-Cath, Inc., v. Mahurkar, 935 F.2d at 1563, 19 U.S.P.Q.2d at 1116. The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function. An antibody described only by functional characteristic, such as antibody that binds PD-1 or one of the claimed epitopes, without any known or disclosed correlation between that function and the structure of the sequence, is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. In re Bell, 991 F.2d 781, 26 U.S.P.Q.2d 1529 (Fed. Cir. 1993). In re Deuel, 51 F.3d 1552, 34 U.S.P.Q.2d 1210 (Fed. Cir. 1995). In the instant case, the specification provides insufficient direction or guidance concerning the relationship between the structure of the possible antibody to demonstrate possession of the breadth of the genus of PD-1 antibodies encompassed by the instant claims, especially in view of the unpredictability of such an endeavor. The prior art as evidenced by Edwards et al., 2003 (instant PTO-892) teaches there is a substantially huge antibody diversity produced to one single antigen target. Edwards provides evidence that over 1000 antibodies, all different amino acid sequences, were generated towards one single protein antigen target (see abstract). Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Without this guidance or direction the skilled artisan would not consider applicant to be in possession of the claimed genus of antibodies because the skilled artisan recognizes that even seemingly minor changes made without guidance or direction as to the relationship between the particular amino acid sequence of the instantly claimed antibody and its ability to bind antigen, can dramatically affect antigen-antibody binding.
Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genus of an antibody that binds PD-1. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester v. G.D. Searle & Co., 358 F.3d 916, 69 USPQ2d 1886 (Fed. Cir. 2004).
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. 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.
What constitutes a "representative number" is an inverse function of the skill and knowledge in the art. Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.
To provide adequate written description and evidence of possession of the claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In the instant case, the only factors present in the claims are a recitation of one generic, broad genus that encompassed a diverse and huge number of possible antibodies that bind the disclosed epitope. The specification does not provide a consistent structure for all of the possible antibodies and fails to provide a representative number of species for the claimed genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that they invented what is claimed.” (See Vas-Cath at page 1116).
With the exception of specifically disclosed antibodies with specific CDRs, the skilled artisan cannot envision the detailed chemical structure of all of the encompassed antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Therefore, claims 16-34 do not meet the written description requirement.
Claims 16-34 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 treating nasopharyngeal carcinomas using toripalimab in combination with gemcitabine and cisplatin, does not reasonably provide enablement for preventing nasopharyngeal carcinomas with any anti-PD-1 antibody in combination with gemcitabine and cisplatin. 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.
MPEP § 2164.01 states:
The standard for determining whether the specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation 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).
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include but are not limited to:
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The breadth of the claims;
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The nature of the invention;
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The state of the prior art;
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The level of one of ordinary skill;
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The level of predictability in the art;
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The amount of direction provided by the inventor;
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The existence of working examples; and
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The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors most relevant to this rejection are 1) the amount of direction provided by the inventor, 2) the existence of working examples and 3) undue experimentation. In the instant case, the amount of direction provided by the inventor and existence of working examples disclosed in the specification, as filed, would not be sufficient to enable the skilled artisan to make and/or use the claimed invention at the time the application was filed without undue experimentation.
(1) The amount of direction provided by the inventor - The amount of guidance or direction needed to enable an 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 “amount of guidance or direction” refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004). Due to the high level of unpredictability in preventing cancers, the skilled artisan would need significant guidance in preparing the invention as a preventative measure. The skilled artisan recognizes that preventing cancers is an intractable proposition, if not now wholly impossible, given, for example, that no specific cause of the cancer is claimed. It is generally recognized that a disease cannot be prevented unless and until its causes are fully appreciated and understood to a degree that it becomes possible to intercede effectively to block its onset or development by any cause.
(2) The existence of working examples - As stated above the specification reasonably provides enablement for an anti-PD-1 antibody that may be used to treat nasopharyngeal carcinomas; however, there is no showing in the specification of any means by which one skilled in the art could prepare a treatment to prevent nasopharyngeal carcinomas. Additionally, the state of the art does not clearly outline metrics or guidelines to predict an individual’s propensity to develop nasopharyngeal carcinomas and prevent its onset, thus making the target of the treatment unclear as it is impossible to know if a person in the general public will develop one of the diseases listed with certainty and also qualify as a candidate for treatment using the instant invention. Therefore, one skilled in the art would be subject to undue experimentation to practice the instant invention as it is currently claimed.
(3) Undue experimentation – The instant claims 16-21 and 26-33 cover a large number of unknown and undefined antibodies specific for PD-1 as long as they are capable of performing the claimed function. Instant claims 22-25 and 34 recite claim language that broadens the scope of the claimed sequences to include undefined and undisclosed variants. Further, these claimed antibodies encompass any possible future discoveries of any possible antibodies with the claimed functions. When claims depend on a recited property (reducing binding to particular domain(s)), a fact situation comparable to Hyatt is possible, where the claim covers every conceivable structure (means) for achieving the stated property (result) while the specification discloses at most only those known to the inventor. See also Fiers v. Sugano, 984 F.2d 164, 25 USPQ2d 1601 (Fed. Cir. 1993) and MPEP §2164.08(a). Therefore, the specification fails to provide enough guidance for one skilled in the art on how to practice the instant method except for the instant examples, thereby requiring trial and error experimentation to identify antibodies meeting the functional limitations of the claims.
As set forth above, inadequate guidance is presented in the specification to overcome the obstacles in practicing the claimed invention in its full scope. The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. Given the tremendous breath of scope involving the instant claims, it would require undue experimentation for one of skill in the art to practice the claimed invention in its full scope. Therefore, the specification fails to provide enough guidance for one skilled in the art on how to practice the instant method, thereby requiring trial and error experimentation to identify antibodies or recombinant proteins meeting the functional limitations of the claims. The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed.
In conclusion upon careful consideration of the Wands factors that are used to determine whether undue experimentation is required to practice an invention, the amount of direction provided by the inventor, undue experimentation, and the working examples provided, as filed, is not deemed sufficient to enable the skilled artisan to make and/or use the invention commensurate in scope with the instant claims at the time the application was filed without undue experimentation.
Applicant is informed that the instant rejection under 35 U.S.C. 112 (a) may be overcome by amending the claims to remove the recitation of “preventing.”
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 16-34 are rejected under 35 U.S.C. 103 as being unpatentable over Wei et al. (in instant PTO-892), in view of Zhang et al. 2016 (in instant PTO-892), and Keam et al. 2019 (in instant PTO-892).
Regarding instant claim 16, Wei et al. discloses the results of a phase I study of toripalimab in patients with refractory malignant solid tumors, and that the eligible patients “were diagnosed with treatment-refractory, stage IV malignant tumors at enrollment. The cancer types they suffered from included nasopharyngeal carcinoma (6/25, 24.0%), …, pharyngeal squamous cell carcinoma (1/25, 4.0%), … Additionally, 16 (64.0%) patients had at least 2 prior lines of chemotherapy. Until data cut-off time of 24th January 2018, the median treatment period was 57 days (range: 1-550 days).The median dose intensity explored was 1.500 mg/kg/week (range: 0.128-5.000 mg/kg/week). The median follow-up time was 5.0 months (range: 1.5-19.8 months)”, see page. 349.
Regarding instant claim 17, Wei et al. teaches that the eligible patients were “adults with histologically confirmed, treatment-refractory, advanced, solitary malignant tumors”, see Abstract.
Regarding instant claims 18 and 19, Wei et al. also teaches that the cancers had positive PD-L1 expression, denoting through immunohistochemical staining analysis that they found “a positive PD-L1 expression was defined as ≥5% membrane staining of any intensity on tumor cells or tumor-infiltrating immune cells”, see page 348.
Regarding instant claims 22-25 and 34, Wei et al. teaches the antibody referred to as “toripalimab” which is the same antibody as recited in the instant invention and encompasses instant SEQ ID NOs: 1-10. The instant specification discloses on pages 5-6 that the sequences SEQ ID NOs: 1-10 belong to the antibody known as “toripalimab”.
Regarding instant claim 26, Wei et al. teaches that “toripalimab was intravenously infused every 2 weeks in dose-escalating cohorts at 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, and 240 mg. The study followed standard 3 + 3 design”, see Abstract.
Wei et al. also postulates future uses of the anti-PD-1 antibody, “which was well tolerated and demonstrated anti-tumor activity in treatment-refractory advanced solitary malignant tumors”, see page 352. Wei et al. also recommends further exploration in various tumors and combination therapies, see page 352.
However, Wei et al. does not explicitly recite combination therapies with gemcitabine and cisplatin. Zhang et al. remedies this deficiency.
Zhang et al. teaches that outcomes are poor for patients with recurrent or metastatic nasopharyngeal carcinoma, and compares the “efficacy and safety of gemcitabine plus cisplatin versus fluorouracil plus cisplatin in patients with recurrent or metastatic nasopharyngeal carcinoma”, see Abstract.
Regarding instant claim 20, the patient eligibility criteria included “patients with histologically or cytologically confirmed nasopharyngeal carcinoma. The histological subtype of nasopharyngeal carcinoma was categorised according to the WHO classification of tumours. Type I is keratinising squamous-cell carcinoma. Type II is differentiated non keratinising carcinoma. Type III is undifferentiated non keratinising carcinoma”, see Methods.
Regarding instant claims 27-33, Zhang et al. teaches “patients with recurrent or metastatic nasopharyngeal carcinoma were recruited from 22 hospitals in China. ... Patients were randomly assigned in a 1:1 ratio to receive either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously on day 1), or fluorouracil (4 g/m2 in continuous intravenous infusion over 96 h) and cisplatin (80 mg/m2 on day 1 given intravenously) once every 3 weeks for a maximum of six cycles… The primary endpoint was progression-free survival assessed by the independent image committee in the intention-to-treat population”, see Methods.
Zhang et al. found that “the median progression-free survival was 7·0 months (4·4-10·9) in the gemcitabine group and 5·6 months (3·0-7·0) in the fluorouracil group (hazard ratio [HR] 0·55 [95% CI 0·44-0·68]; p<0·0001)” and concluded that “gemcitabine plus cisplatin prolongs progression-free survival in patients with recurrent or metastatic nasopharyngeal carcinoma. The results establish gemcitabine plus cisplatin as the standard first-line treatment option for this population”, see Interpretation under Summary.
However, Wei et al. and Zhang et al. do not teach about the role of the Epstein-Barr virus in nasopharyngeal carcinomas. Keam et al. remedies this deficiency.
Keam et al. teaches that the recommended dosage for toripalimab is “3 mg/kg every 2 weeks as an intravenous (IV) infusion until disease progression or unacceptable toxicity”, see Introduction. Keam et al. teaches the use of toripalimab in patients with “refractory or metastatic nasopharyngeal carcinoma who had experienced progression after standard therapy, treatment with IV toripalimab 3 mg/kg every 2 weeks in a phase 2, open-label trial conducted in China (NCT02915432) achieved an ORR of 30.8% (16 partial responses) and a DCR of 61.5% (n = 52 evaluable patients as at January 2018) [15]. ORR in PD-L1 positive tumours was 38.5%”, see page 576.
Regarding instant claim 21, Keam et al. report an “average 47-fold reduction in plasma Epstein Barr virus DNA copy number was seen in patients who responded to treatment with toripalimab”, see page 576.
It would be obvious at the time of the instant invention to use the antibody and dosage regimens taught by Wei et al., which is an effective treatment against nasopharyngeal carcinomas that results in a durable response rate in afflicted patients, with the combination therapy taught by Zhang et al. which treats nasopharyngeal cancers that have failed previous chemotherapy, or require a multifaceted combinatorial approach to targeting cancer cells, with the teachings of Keam et al. which elucidate the role of the Epstein Barr virus in the origins of the cancer. One would be motivated to combine the antibody and dosage regimen, with the additional chemotherapeutics of gemcitabine and cisplatin, with the expectation of treating the cancers effectively. Wei et al. proposes further exploration in various tumors and combination therapies, and Zhang et al. address this common goal by providing further therapeutic options that are proven to be effective against nasopharyngeal carcinomas that are refractory in nature. A person of ordinary skill in the art would have been motivated to combine treatment modalities known to be useful for the same conditions, and would have expected the combination therapy to be at least as good as either therapy alone (see MPEP §2144.06).
The instant claims are amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose (e.g., treating nasopharyngeal carcinomas) in order to form a third composition that is to be used for the very same purpose since the idea of combining them flows logically from their having been individually taught in the prior art. Applying the same logic to the instant claims, given the teachings of the prior art, it would have been obvious to combine the treatments because the idea of doing so would have logically followed from their having been individually taught in the prior art to be useful as anti-cancer agents. One of ordinary skill in the art would have reasonably expected to obtain a therapeutic benefit upon the combination of the agents since they had been demonstrated in the prior art to be reasonably predictive of treating nasopharyngeal carcinomas.
Therefore, claims 16-34 are rejected as obvious over Wei et al., Zhang et al., and Keam et al.
Conclusion
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/SELAM BERHANE/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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