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 .
Status of Claims
Applicant’s amendment filed February 13, 2024 is acknowledged. Claims 1,3-9, 11, 13, 15, 22, 24 have been amended. Claims 25-28 are new. Claims 10, 12, 14, 16-18, 20 and 23 have been canceled. Claims 1-9, 11,13, 15, 19, 21-22, and 24-28 are pending. Applicant's election of Group I, claims 1-9, 11, 13, 15, 19, 21, 22 and 24 in the reply filed on March 6, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Specification Objections
The use of the term PacBio [paragraph 0070], which is a trade name or a mark 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. Applicant should review the specification for additional trademarks. Correction is required.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered. Correction is required.
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 1-9, 11, 13, 15, 19, 21, 22 and 24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus.
The instant claims are drawn to a method of preventing or treating acute GVHD(aGVHD) in a subject receiving a hematopoietic cell transplantation (HCT) or autoimmune colitis comprising administering to the subject an effective amount of an anti-IL-22 antibody, an anti-IL-6 antibody, donor-type CX3CR1hi MNPs, donor-type NK cells, a ceacam-1 antagonist, an anti-Gr-1 antibody or a combination thereof.
The specification discloses that the invention is directed to a method of preventing or treating aGVHD in a subject receiving a hematopoietic cell transplantation (HCT) or autoimmune colitis. The method entails administering to the subject an effective amount of an anti-IL-22 antibody, an anti-IL-6 antibody, donor-type CX3CR1h' MNPs, donor-type NK cells, a ceacam-1 antagonist, an anti-Gr-1 antibody, or a combination thereof. In certain embodiments, the ceacam-1 antagonist is an anti-ceacam 1 antibody. In certain embodiments, the anti-IL-22 antibody, the anti-IL-6 antibody, the anti-ceacam 1 antibody, or the anti-Gr-1 antibody is a monoclonal antibody. In certain embodiments, the anti-IL-22 antibody, the anti-IL-6 antibody, the anti-ceacam 1 antibody, or the anti- Gr-1 antibody is a recombinant antibody. In certain embodiments, the anti-IL-22 antibody, the anti-IL-6 antibody, the anti-ceacam 1 antibody, or the anti-Gr-1 antibody is a human antibody. In certain embodiments, the anti-IL-22 antibody, the anti-IL-6 antibody, the anti-ceacam 1 antibody, or the anti-Gr-1 antibody is a humanized antibody.
There are two main issues with regards to written description of the instant claims.
First, the claimed invention encompasses any anti-IL-22 antibody, an anti-IL-6 antibody, donor-type CX3CR1hi MNPs, donor-type NK cells, a ceacam-1 antagonist, an anti-Gr-1 antibody or a combination thereof. This would represent a large pool of variant antibodies that must have similar functional activity. There is no limit in the claims, as written, that the variance be contiguous. The specification provides limited guidance regarding which amino acids can be modified in the genus of antibodies, while maintaining any given function.
The first paragraph of 35 U.S.C. § 112 "requires a 'written description of the invention' which is separate and distinct from the enablement requirement." Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563 (Fed. Cir. 1991). An adequate written description of a chemical invention "requires a precise definition, such as by structure, formula, chemical name, or physical properties." University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004); Regents of the Univ. of Cal. v. Eli Lilly & Co., Inc., 119 F.3d 1559, 1566 (Fed. Cir. 1997); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993). "A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F.3d at 923; Eli Lilly, 119 F.3d at 1568. Instead, the "disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described." Id. In addition, possession of a genus "may be achieved by means of a recitation of a representative number of [compounds]... falling within the scope of the genus." Eli Lilly, 119 F.3d at 1569. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus. See Rochester, 358 F.3d at 927.
Thus, case law dictates that to provide evidence of possession of a 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 this case, the method of treatment or prevention use a plurality of antibodies that do not have a defined structure. There is not even identification of any particular portion of a structure that must be conserved or required. Not a single species of the encompassed genus is described in the specification with regard to its precise structure. Rather, the specification provides methods of screening for antibody products. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the genus of antibody products recited in the claims.
Regarding structure-function correlation more specifically, it is noted that one of skill in the art was aware that there is a lack of structure-function correlation in antibody molecules. Evidence of such in the form of publications in the art include the following.
The prior art recognizes that the full six CDR sequences are required to form the part of an antibody, i.e., the paratope, that specifically binds the target antigen. See Al Qaraghuli et al. (2020, Nature Scientific Reports 10:13969), who state that the six CDRs form a continuous surface to form the paratope that binds the epitope of the cognate antigen.
However, the prior art also recognizes that a single protein can be bound by a very large and structurally diverse genus of antibodies (i.e., there is no common structural relationship even for antibodies that bind to the same protein, epitope, or overlapping epitopes). For example, Edwards et al. (2003, JMB 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences, and representative of almost the entire extensive heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines), and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well.
Lloyd et al. (2009, Protein Engineering, Eng. Design & Selection 22(3): 159-168) teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding. Said reference further teaches that in their studies, of the 841 unselected and 5,044 selected antibodies sequenced, all but one of the 49 functional VH gene segments was observed, and that there are on average about 120 different antibodies generated per antigen. Said reference also teaches that a wide variety of VH and VL pairings further increase diversity. (See entire reference.)
Goel et al. (2004, J. Immunol. 173: 7358-7367) teach that three mAbs that bind to the same short (12-mer) peptide, exhibit diverse V gene usage, indicating their independent germline origin. Said reference further teaches that two of these mAbs recognize the same set of amino acid residues defining the epitope (alternate amino acid residues spread over the entire sequence), however, the relative contribution of each set of residues in the peptide showed significant variation. The reference notes that all of the mAbs do not show any kind of V gene restriction among themselves, implying variable paratope structure, despite that two of these mAbs bind to the peptide through a common set of residues. (See entire reference).
Khan et al. (2014, J. Immunol. 192: 5398-5405) teach that two structurally diverse germline mAbs recognizing overlapping epitopes of the same short peptide do so in different topologies, the antibodies possessing entirely different CDR sequences. Said reference teaches that unrelated mAbs structurally adjust to recognize an antigen, indicating that the primary B cell response is composed of BCRs having a high degree of structural adaptability. Said reference also teaches that the common epitope(s) also adopt distinct conformations when bound to different mAbs, with the higher degree of structural plasticity inherent to the mAbs. Said reference further teaches “It has been shown that both the framework region and the CDRs have a considerable amount of inherent conformational plasticity...Therefore, it is not surprising that distinct germline Abs recognize the same epitope by rearranging the CDR conformations. This may well have implications of Ag specificity beyond the naive BCR repertoire, because Kaji et al (JEM, Vol. 209, No,11, 2080-2097)-... .have shown in a recent report that the B cell memory can contain both germline-encoded and somatically mutated BCRs.” (See entire reference).
Poosarla et al. (2017, Biotechn. Bioeng. 114(6): 1331 -1342) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Rabia, et al. (2018, Biochemical Engineering Journal 137:365-374) teach what effects mutations can have on an antibody's stability, solubility, binding affinity and binding specificity. Rabia et al. report that an increase in antibody affinity can be associated with a decrease in stability (p. 366, col. 2 last paragraph; Fig. 2). Rabia et al. thus teach that affinity and specificity are not necessarily correlated and that and increase in affinity does not indicate an increase in specificity (Fig. 3; p. 368, col. 1, section 3,1st full paragraph to col. 2, 2nd full paragraph).
Conversely, evidence also shows that some functionally diverse antibodies can share some structural similarities, including an entire CDR region. See Igawa et al. (US 9,334,331 B2), who disclose antibody Q153 that binds human Factor IXa. Q153 comprises a VH-CDR1 identical to the VH-CDR1 of antibody 11E12 disclosed by Gonzales et al. (US 10,421,807 B2). However, 11E12 specifically binds canine IL-31, a protein having no structural or functional similarity to human Factor IXa. This illustrates that even when some CDR regions share 100% structural identity, the antibodies in which they are comprised can have completely different functions (i.e., binding specificities).
The combination of evidentiary publications thus underscores a lack of structure-function correlation in antibody molecules.
Regarding a representative number of species more specifically, the instant specification fails to describe a representative number of species to provide adequate written description of the claimed genus as per MPEP § 2163.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991), 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 [he or she] invented what is claimed.” (See Vas-Cath at page 1116). However, in the instant case the skilled artisan cannot envision the detailed chemical structure of the encompassed antibody products, 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 compound 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 (Fed. Cir. 1991).
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 (BPAI 1993). In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Applicant’s attention is directed to the recent decision in Amgen Inc. v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The court discussed whether an antibody is adequately described by describing a newly characterized antigen. Specifically, the court referred to the decision in Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir. 2011). In that case, the patentee claimed a genus of antibodies containing a human variable region that has particularly desirable therapeutic properties: high affinity, neutralizing activity, and A2 specificity. Despite the fact that the specification disclosed human TNF-α protein, and despite the disclosure of the structures of more than one species of antibody related to the genus, the court ruled that that the generic antibody claims at issue were invalid for lack of written description. The fact pattern is similar in the instant case, although in this case there is no description of the structure of a single antagonist antibody recited by the claims. As in the court case, the instant claims recite a genus of antibodies that have affinity for those antigens and have a desirable therapeutic property, i.e., antagonizing activity and the ability to inhibit binding of sclerostin to LRP. Following the finding in Centocor, the instant claims are found to lack adequate written description.
The court in Amgen v. Sanofi further compares the requirements of enablement and written description, stating that:
“We cannot say that this particular context, involving a “newly characterized antigen” and a functional genus claim to corresponding antibodies, is one in which the underlying science establishes that a finding of “make and use” (routine or conventional production) actually does equate to the required description of the claimed products. For us to draw such a conclusion, and transform a factual issue into a legally required inference, we would have to declare a contested scientific proposition to be so settled as to be entitled to judicial notice. That we cannot do.”
The court indicated that it has been hotly disputed whether or not knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. Citing Centocor again, the court provides an analogy for the antibody-antigen relationship as not quite a lock and key relationship but rather providing a lock and then searching for a key on a ring with a million keys on it. The court concludes that the “newly characterized antigen” test flouts basic legal principles of the written description requirement, reasoning that section 112 requires a written description of the invention, whereas the newly characterized antigen test allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen. The court urges that such constricts the “quid pro quo” of the patent system where one describes an invention in order to obtain a patent.
Similarly, in Juno Therapeutics, Inc., Sloan Kettering Institute for Cancer Research v. Kite Pharma, Inc. (Case 2020-1758, CAFC August 2021), the court found that the disclosure of two antibody products (scFv molecules) was insufficient to support written description for the claimed genera, specifying that the specification at issue failed to disclose “structural features common to the members of the genus to support that the inventors possessed the claimed invention;” i.e., the specification and evidence of record failed to provide a structure-function correlation. In the instant case, there is also no evidence of a structure-function correlation for antibodies, and thus the claims are properly rejected for lack of adequate written description.
Finally, for a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), “[claiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
Second, the specification has failed to support the use of the term “preventing”. The claims are drawn to a method of preventing or treating acute GVHD(aGVHD) in a subject receiving a hematopoietic cell transplantation (HCT) or autoimmune colitis comprising administering to the subject an effective amount of an anti-IL-22 antibody, an anti-IL-6 antibody, donor-type CX3CR1hi MNPs, donor-type NK cells, a ceacam-1 antagonist, an anti-Gr-1 antibody or a combination thereof.
The specification discloses "treating" or "treatment" of a disease or a condition may refer to preventing the disease or condition, slowing the onset or rate of development of the disease or condition, reducing the risk of developing the disease or condition, preventing or delaying the development of symptoms associated with the disease or condition, reducing or ending symptoms associated with the disease or condition, generating a complete or partial regression of the disease or condition, or some combinations thereof. The specification definition of treating includes the “generating a complete or partial regression of the disease or condition”. The specification does not provide written description for a complete a method of a method of preventing or treating acute GVHD(aGVHD) in a subject receiving a hematopoietic cell transplantation (HCT) or autoimmune colitis comprising administering to the subject an effective amount of various antibodies. The specification disclose that at [paragraph 0120],
“As demonstrated in the working examples, expansion of Th/Tc22 cells in the colon tissues is in association with SR-Gut-GVHD in patients. With murine models, the intestinal epithelial cells of SR-Gut-GVHD recipients upregulated expression of ceacam-1, and ceacam-1 deficiency in the intestinal epithelial cells effectively prevented SR-Gut-GVHD in association with enhanced trans-differentiation of Th/Tc22 into FoxP3+ Treg cells in the MLN as well as increase of Treg cells and decrease of Th/Tc1 and Th/Tc22 cells in the colon tissues. The ceacam-1 deficiency in the intestinal epithelial cells also blocked interaction between bacteria and intestinal epithelial cells and reduced bacterial colony formation at the epithelial cell area and reverses dysbiosis. Administration of anti-ceacam-1 in combination of depletion of neutrophils that express high levels of ceacam-1 effectively prevented and reversed SR-Gut-GVHD, although treating acute GVHD with anti-Gr-1 to deplete neutrophils is not practical for acute GVHD patients due to concerns about increase of infection. These results indicate that blockade of homophilic ceacam-1 interactions between bacteria and intestinal epithelial cells via oral administration of ceacam-1 antagonist may be an effective approach for preventing and treating SR-Gut-GVHD and even general Gut-GVHD”.
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 (see MPEP 2163). A patent specification must set forth enough detail to allow a person of ordinary skill in the art to understand what is claimed and to recognize that the inventor invented what is claimed. In the case of DNA, an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention (see Lilly, 119 F.3d at 1566 (quoting Fiers, 984 F.2d 15 1171 ). Because the specification does not describe the amino acid sequences nor any core structures for potentially numerous different antibody amino acid sequences which would have the recited functions, one of skill in the art would reasonably conclude that applicant was not in possession of the claimed genus of all anti-CD122 antibodies which bind to CD122 and modulate immune function and ADA formation.
Therefore, neither the art nor the specification provide a sufficient representative number of antibodies, a sufficient structure-function correlation or a method of a method of preventing or treating acute GVHD(aGVHD) in a subject receiving a hematopoietic cell transplantation (HCT) or autoimmune colitis comprising administering to the subject an effective amount of various antibodies to meet the written description requirements.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the 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 Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
No claims allowed.
Conclusion
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/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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