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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 17, 2026 has been entered.
Detailed Action
This action is in response to the papers filed March 17, 2026.
Amendments
Applicant has cancelled Claims 2-5, 8-9, 15-16, 19-29, 31-34, and 36-50, amended Claims 1 and 14, and withdrawn Claims 6-7, 10-13, 17-18, 30, and 35.
Claims 1, 6-7, 10-14, 17-18, 30, and 35 are pending.
Allowable Subject Matter
1. Claim 1 is allowed.
The following is a statement of reasons for the indication of allowable subject matter:
Applicant has amended the claim to recite a Bi-specific Natural Killer and Neutrophil Engager (BiKE) molecule comprising the amino acid sequence of SEQ ID NO:4 (533 amino acids).
SEQ ID NO:4 encodes:
i) an scFv which binds to CD138, and
ii) an scFv which binds to CD16,
(syn. CD138xCD16 or CD16xCD138).
Morrison (U.S. 2016/0115239; of record) is considered relevant prior art for having disclosed an anti-CD138 antibody comprising a signal peptide (e.g. Example 1, SEQ ID NO:48) that is 100% identical to amino acids 1-20 of instant SEQ ID NO:4 and an anti-CD138 light chain variable region ([0236], SEQ ID NO:53, lower line) that is 100% identical to amino acids 21-127 of instant SEQ ID NO:4 comprising the anti-CD138 LCDR1-3 SEQ ID NO’s:13-15 present in instant SEQ ID NO:4 (upper line), as shown below:
MKSQTQVFIFLLLCVSGAHGDIQMTQSTSSLSASLGDRVTISCSASQGINNYLNWYQQKP
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
MKSQTQVFIFLLLCVSGAHGDIQMTQSTSSLSASLGDRVTISCSASQGINNYLNWYQQKP
DGTVELLIYYTSTLQSGVPSRFSGSGSGTDYSLTISNLEPEDIGTYYCQQYSKLPRTFGG
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
DGTVELLIYYTSTLQSGVPSRFSGSGSGTDYSLTISNLEPEDIGTYYCQQYSKLPRTFGG
GTKLEIK
|||||||
GTKLEIK
Morrison disclosed an anti-CD138 antibody comprising an anti-CD138 heavy chain variable region ([0236], SEQ ID NO:52, lower line) that is 100% identical to amino acids 144-265 of instant SEQ ID NO:4 comprising the anti-CD138 HCDR1-3 SEQ ID NO’s:10-12 present in instant SEQ ID NO:4 (upper line), as shown below:
QVQLQQSGSELMMPGASVKISCKATGYTFSNYWIEWVKQRPGHGLEWIGEILPGTGRTIY
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
QVQLQQSGSELMMPGASVKISCKATGYTFSNYWIEWVKQRPGHGLEWIGEILPGTGRTIY
NEKFKGKATFTADISSNTVQMQLSSLTSEDSAVYYCARRDYYGNFYYAMDYWGQGTSVTVSS
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
NEKFKGKATFTADISSNTVQMQLSSLTSEDSAVYYCARRDYYGNFYYAMDYWGQGTSVTVSS
Johnson et al is considered relevant prior art for having disclosed bispecific antibodies, wherein at least one domain of the bispecific molecule binds CD16 (e.g. Figure 8).
Johnson et al disclosed wherein the scFv that binds CD16 (e.g. SEQ ID NO:250; lower line) comprises the amino acid sequence that is 100% identical to the CD16 light chain variable region of instant SEQ ID NO:4 and comprises one or more of SEQ ID NO’s: 19 (anti-CD16 LCDR1), 20 (anti-CD16 LCDR2), and 21 (anti-CD16 LCDR3; upper line, bolded, underlined, respectively), as shown below:
DTVLTQSPASLAVSLGQRATISCKASQSVDFDGDSFMNWYQQKPGQPPKLLIYTTSNLES
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
DTVLTQSPASLAVSLGQRATISCKASQSVDFDGDSFMNWYQQKPGQPPKLLIYTTSNLES
GIPARFSASGSGTDFTLNIHPVEEEDTATYYCQQSNEDPYTFGGGTKLEIK
|||||||||||||||||||||||||||||||||||||||||||||||||||
GIPARFSASGSGTDFTLNIHPVEEEDTATYYCQQSNEDPYTFGGGTKLEIK
Johnson et al (U.S. 2010/0174053; of record) disclosed wherein the scFv that binds CD16 (e.g. SEQ ID NO:229; lower line) comprises the amino acid sequence that is about 86% identical to the CD16 heavy chain variable region of instant SEQ ID NO:4 and comprises one or more of SEQ ID NO’s: 16 (anti-CD16 HCDR1), 17 (anti-CD16 HCDR2), and 18 (anti-CD16 HCDR3; upper line, bolded, underlined, respectively), as shown below:
QVTLKESGPGILQPSQTLSLTCSFSGFSLRTSGMGVGWIRQPSGKGLEWLAHIWWDDDKR
||||:|||| :::|:|||:|||:|||||| |||||||||||| || ||||||||||||||
QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGKALEWLAHIWWDDDKR
YNPALKSRLTISKDTSSNQVFLKIASVDTADTATYYCAQINPAWFAYWGQGTLVTVSA
|||||||||||||||| ||| | : ::| |||||||||||||||||||||||||||:
YNPALKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCAQINPAWFAYWGQGTLVTVSS
Kang et al (U.S. 2018/0021378; published January 25, 2018; of record) is considered relevant prior art for having disclosed a bi-specific antibody BiKE (e.g. [0012]; claim 11) comprising a first scFv ([0012]; claim 12) antigen binding domain that binds CD138 (e.g. [0012]; claim 13) and a second scFv (claim 12) antigen binding domain that binds CD16 (e.g. [0012]; claim 14).
The prior art does not appear to teach or fairly suggest the amino acid sequence of SEQ ID NO:4.
Rejoinder
2. Claim 1 is allowable. The restriction requirement between Groups II-III, as set forth in the Office action mailed on March 28, 2025, has been reconsidered in view of the allowability of claims to the elected invention pursuant to MPEP § 821.04(a). The restriction requirement is hereby withdrawn as to any claim that requires all the limitations of an allowable claim. Claims 30 and 35, directed to previously non-elected Groups are no longer withdrawn from consideration because the claim(s) requires all the limitations of an allowable claim.
In view of the above noted withdrawal of the restriction requirement, applicant is advised that if any claim presented in a continuation or divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Election/Restrictions
Applicant has elected without traverse the invention of Group I, claim(s) 1-2, 5-13, and 16-18, drawn to a MYXV whose genome comprises a transgene that encodes a multi-specific immune cell engager.
Within Group I, Applicant has elected the following species, wherein:
i) the alternative immune cell engager transgene is a BiKE that binds CD16 and CD138, as recited in Claims 2, 5, and 8-9.
In a telephone conversation with Applicant’s representative, Pallab Singh at 215-268-3759 on June 4, 2025, it was confirmed that Applicant has elected the alternative SEQ ID NO to be SEQ ID NO:4.
In light of the cited prior art below, the Examiner withdraws the species elections between SEQ ID NO’s: 4, 16, 17, 18, 19, 20, and 21, as SEQ ID NO’s 16-21 are present in SEQ ID NO:4.
Claims 1, 6-7, 10-14, 17-18, 30, and 35 are pending.
Claims 6-7, 10-13, and 17-18 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1, 14, 30, and 35 are under consideration.
The Examiner notes that Claims 6-7, 10-13, and 17-18 are directed to different molecules than the BiKE of Claim 1. Applicant should cancel these claims, to be pursued in a divisional application.
Priority
This application is a 371 of PCT/US2020/055073 filed on October 9, 2020. Applicant’s claim for the benefit of a prior-filed application provisional application 62/913,655 filed on October 10, 2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
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.
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.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
3. The prior rejection of Claim 3 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in light of Applicant’s cancellation of the claim.
4. The prior rejection of Claim 9 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in light of Applicant’s cancellation of the claim.
5. The prior rejection of Claims 1, 3, 9, and 14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn in light of Applicant’s amendment to Claim 1 to recite wherein the BiKE comprises SEQ ID NO:4.
6. Claim 14 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 1 to recite wherein the BiKE comprises SEQ ID NO:4.
Claim 14 recites wherein the BiKE comprises one or more scFvs derived from an anti-human CD antibody.
As a first matter, Claim 1 is directed to a bi-specific (“bi” = “two”) molecule. Thus, the phrase “or more” in Claim 14 is broader in scope than Claim 1.
As a second matter, Claim 1 is directed to SEQ ID NO:4.
The recitation of a process limitation in Claim 14 is not viewed as positively limiting the claimed product absent a showing that the process of making recited in Claim 14 imparts a novel or unexpected property to the claimed product, as it is assumed that equivalent products are obtainable by multiple routes. The burden is placed upon the applicants to establish a patentable distinction between the claimed and referenced products. The method in which the BiKE molecule comprising SEQ ID NO:4 was produced is immaterial to their patentability. The structure of SEQ ID NO:4 has not changed in Claim 14.
"Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 227 USPQ 964, 966 (Fed. Cir. 1985). See also MPEP §2113.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
7. Claim 35 is 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.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “leukocyte” in Claim 35 is used by the claim to encompasses a genus of structurally and functionally different cell types, including, but not limited to, monocytes, lymphocytes, B cells, plasma cells, T cells, neutrophils, basophils, eosinophils, megakaryocytes, NK cells, NKT cells, mast cells, innate lymphoid cells, common myeloid precursors, common lymphoid precursors, myeloblasts, monoblasts, promonocytes, lymphoblasts, prolymphocytes, hemocytoblasts, megakaryoblasts, promegakaryocytes, stem cells, pro B cells, pre B cells, precursors thereof, or any combination thereof (e.g. [0172]),
while the accepted meaning is monocytes, lymphocytes, B cells, T cells, neutrophils, basophils, eosinophils, megakaryocytes, NK cells, and NKT cells (e.g. Wikipedia, White blood cells; en.wikipedia.org/wiki/White_blood_cell; last visited March 20, 2026).
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The term is indefinite because the specification does not clearly redefine the term.
8. Claims 30 and 35 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.
Claim 30 recites a method of treating a hematological cancer in a subject, the method comprising the step of administering to the subject a composition comprising a myxomavirus whose genome comprises a transgene encoding a BiKE molecule comprising the amino acid sequence of SEQ ID NO:4.
Claim 35 recites a method of treating a hematological cancer in a subject, the method comprising the step of administering to the subject a composition comprising a leukocyte comprising or associated with a myxomavirus whose genome comprises a transgene encoding a BiKE molecule comprising the amino acid sequence of SEQ ID NO:4.
Because “comprises” speaks to the leukocyte actually being infected/transduced with the myxomavirus, the phrase “associated with” is interpreted to refer to the leukocyte that is physically separate from the myxomavirus, e.g. not infected or transduced with the myxomavirus.
It is understood that in order to meaningfully treat the subject, and thereby satisfy the requirements of 35 U.S.C. 101 (See MPEP 2107.01 III, Therapeutic or Pharmacological Utility), a therapeutically effective amount or dose of the myxomavirus of Claim 1 and/or the leukocyte infected/transduced with said myxomavirus must be administered to the subject, thereby achieving some real-world, clinically meaningful therapeutic effect, and thereby being of “immediate benefit to the public”.
The phrase “an effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In reFredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c)
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of subject human or non-human animal to be treated [parameter 1];
the type of viral or cellular pharmaceutical to be administered [parameter 2];
the dosage administered [parameter 3];
the administration route [parameter 4];
the disease/disorder/condition to be treated [parameter 5]; and
the phenotypic response to be achieved [parameter 6].
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition comprising the myxomavirus and/or leukocyte comprising the myxomavirus that, upon administration to the subject, is not, in fact, “a therapeutically effective amount” (syn. a subtherapeutic dose).
Parameter 1
The claims are broad for reasonably encompassing an enormous genus of animal subjects, including, but not limited to, birds, poultry, chickens, ducks, geese, turkeys, mammals, human, primate, mammals, cattle, pigs, horses, sheep, cats, dogs, mice, and rats (e.g. [0049]).
The claims are broad for encompassing about 1,000,000 species of animals (Kingdoms of Life, waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021), wherein the mammalian sub-genus reasonably encompasses some 6,400 species (including humans), distributed in about 1,200 genera, about 152 families and about 29 orders (Mammal, en.wikipedia.org/wiki/Mammal, last visited August 31, 2022).
Parameter 2
The claimed pharmaceutical compositions are:
i) a myxomavirus whose genome comprises a transgene encoding a BiKE molecule comprising the amino acid sequence of SEQ ID NO:4;
ii) a leukocyte infected/transduced with said myxomavirus of (i); and
iii) a leukocyte that is physically separate from the myxomavirus, syn. not infected or transduced with the myxomavirus of (i).
The specification discloses “leukocyte” encompasses a genus of structurally and functionally different cell types, including, but not limited to, monocytes, lymphocytes, B cells, plasma cells, T cells, neutrophils, basophils, eosinophils, megakaryocytes, NK cells, NKT cells, mast cells, innate lymphoid cells, common myeloid precursors, common lymphoid precursors, myeloblasts, monoblasts, promonocytes, lymphoblasts, prolymphocytes, hemocytoblasts, megakaryoblasts, promegakaryocytes, stem cells, pro B cells, pre B cells, precursors thereof, or any combination thereof (e.g. [0172]).
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection because, absent objective evidence to the contrary, the term “leukocyte” in the claim encompasses cell types that are not art-recognized “leukocytes”, e.g. mast cells, innate lymphoid cells, common myeloid precursors, common lymphoid precursors, myeloblasts, monoblasts, promonocytes, lymphoblasts, prolymphocytes, hemocytoblasts, megakaryoblasts, promegakaryocytes, stem cells, pro B cells, pre B cells, and precursors thereof.
Parameter 3
The claimed methods are recited at a high level of generality for the myxomavirus dosage and/or leukocyte dosage that is to be administered.
The claims literally recite the minimal dosage to be:
i) just one(!) myxomavirus (Claim 30);
ii) just one(!) leukocyte infected/transduced with the myxomavirus (Claim 35); or
iii) just one(!) leukocyte in combination with just one(!) myxomavirus (Claim 35).
To the extent that more than one myxomavirus and/or leukocyte may be administered, the claims encompass myxomavirus dosages including, but not limited to, as little as 1x10^2 to 1x10^20 vector genomes (e.g. [0155]), or more, for example.
[0048] discloses the effective amounts vary with additional contextual parameters including, but not limited to, age of the subject, general condition of the subject, the severity of the condition to be treated, the particular pharmaceutical being administered, the duration of treatment, the nature of concurrent treatment, and the pharmaceutically acceptable carrier.
[0153] discloses the virus dosage will vary depending upon the virulence of the particular myxomavirus strain that is to be administered, as well as the nature of cells that are to be targeted.
[0175] discloses the leukocytes can be exposed to the myxomavirus at any ratio.
While [0175-183] disclose the leukocytes are contacted with or whose surfaces are adsorbed to the myxomavirus, instant Claim 35 fails to recite this limitation. Instant recitation “associated with” is broader in scope than “contacted” or “adsorbed”, because “associated with” does not require the physical contact between the leukocyte and the myxomavirus.
Parameter 4
The claimed methods are recited at a high level of generality for the multitude of anatomically distinct administration routes (e.g. [0161, 191]), including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic (e.g. High et al (U.S. 2015/0111955, [0077]).
Parameter 5
The claims are broad for reasonably encompassing an enormous genus of etiologically and pathologically distinct hematological cancers disorders recited at a high level of generality, including, but not limited to the lengthy genus disclosed in [0044] (pgs 10-11).
Parameter 6
The claims are broad for reasonably encompassing an enormous genus of physiologically and phenotypically different results, which evokes the question: A therapeutically effective amount to do what?
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition comprising the myxomavirus and/or leukocyte comprising the myxomavirus that, upon administration to the subject, is not, in fact, “a therapeutically effective amount” (syn. a subtherapeutic dose).
The specification discloses, for example:
i) reduce, essentially reduce (whereby “essentially” is an arbitrary and subjective determination), or eliminate refractory and drug-resistant Multiple Mylemoma [0039];
ii) to produce a desired effect, which can be a beneficial effect [0048], whereby “desired” and “beneficial” is/are arbitrary and subjective determinations;
iii) delaying or inhibiting the development of the disease or condition, delaying or inhibiting the progression of the disease or condition [0056];
iv) ameliorates, meaning any observable beneficial effect, a sign or symptom of the disease or pathological condition after it has begun to develop [0056];
v) reducing in severity one or more clinical symptoms [0056];
vi) slowing progression of disease, including metastasis [0056];
vi) improvement in overall health or well-being of the subject [0056]; and
vii) decreasing the risk of developing pathology, e.g. metastatic cancer [0056].
The recitation implies a genus of unrecited and undisclosed phenotypes by which the therapeutically effective dose is to be determined and/or identified, thereby rendering the claim indefinite. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
Appropriate correction is required.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
9. Claims 30 and 35 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.
Claim 30 recites a method of treating a hematological cancer in a subject, the method comprising the step of administering to the subject a composition comprising a myxomavirus whose genome comprises a transgene encoding a BiKE molecule comprising the amino acid sequence of SEQ ID NO:4.
Claim 35 recites a method of treating a hematological cancer in a subject, the method comprising the step of administering to the subject a composition comprising a leukocyte comprising or associated with a myxomavirus whose genome comprises a transgene encoding a BiKE molecule comprising the amino acid sequence of SEQ ID NO:4.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and 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. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of subject human or non-human animal to be treated [parameter 1];
the type of viral or cellular pharmaceutical to be administered [parameter 2];
the dosage administered [parameter 3];
the administration route [parameter 4];
the disease/disorder/condition to be treated [parameter 5]; and
the phenotypic response to be achieved [parameter 6].
The claim(s) also denote(s) that there is an amount of the pharmaceutical composition comprising the myxomavirus and/or leukocyte comprising the myxomavirus that, upon administration to the subject, is not, in fact, “a therapeutically effective amount” (syn. a subtherapeutic dose).
Examples 12-14 are merely prophetic in vivo examples, disclosed at a high level of generality.
There is no disclosure of a therapeutically effective amount of the genus of leukocytes infected/transduced with, nor in combination with, the myxomavirus, to necessarily and predictably achieve a real-world, clinically meaningful therapeutic treatment of a hematological cancer in the enormous genus of about 1x10^6 human and non-human animal subjects.
Claims literally recite the minimal dosage to be:
i) just one(!) myxomavirus (Claim 30);
ii) just one(!) leukocyte infected/transduced with the myxomavirus (Claim 35); or
iii) just one(!) leukocyte in combination with just one(!) myxomavirus (Claim 35).
While Example 16 discloses a mouse multiple myeloma animal model in which a myxomavirus is administered (e.g. [0281]), the Example fails to disclose the dosage of the myxomavirus administered, let alone the route of administration.
Those of ordinary skill in the art would immediately recognize that one simply cannot extrapolate the necessary working parameters of 1, 2, 3, 4, 5, and 6 above from such an obfuscatory disclosure.
The specification fails to disclose a working example of administering via the enormous genus of anatomically distinct routes [parameter 4] a pharmaceutical composition comprising just one(!) myxomavirus (Claim 30) [parameter 2, parameter 3] in a method of treating the enormous genus of about 1x10^6 human and non-human animal subject [parameter 1] suffering from the enormous genus of etiologically and pathologically distinct hematological cancers [parameter 5] so as to necessarily and predictably achieve a real-world and clinically meaningful therapeutic result [parameter 6], including, but not limited to:
i) reducing, essentially reducing, or eliminating refractory and drug-resistant Multiple Mylemoma;
ii) producing a desired or beneficial effect;
iii) delaying or inhibiting the development of the disease or condition, delaying or inhibiting the progression of the disease or condition;
iv) ameliorating any observable beneficial effect, a sign or symptom of the disease or pathological condition after it has begun to develop;
v) reducing in severity one or more clinical symptoms;
vi) slowing progression of disease, including metastasis;
vi) improving in overall health or well-being of the subject; and/or
vii) decreasing the risk of developing pathology, e.g. metastatic cancer.
The specification fails to disclose a working example of administering via the enormous genus of anatomically distinct routes [parameter 4] a pharmaceutical composition comprising just one(!) leukocyte infected/transduced with the myxomavirus (Claim 35) [parameter 2, parameter 3] in a method of treating the enormous genus of about 1x10^6 human and non-human animal subject [parameter 1] suffering from the enormous genus of etiologically and pathologically distinct hematological cancers [parameter 5] so as to necessarily and predictably achieve a real-world and clinically meaningful therapeutic result [parameter 6], including, but not limited to:
i) reducing, essentially reducing, or eliminating refractory and drug-resistant Multiple Mylemoma;
ii) producing a desired or beneficial effect;
iii) delaying or inhibiting the development of the disease or condition, delaying or inhibiting the progression of the disease or condition;
iv) ameliorating any observable beneficial effect, a sign or symptom of the disease or pathological condition after it has begun to develop;
v) reducing in severity one or more clinical symptoms;
vi) slowing progression of disease, including metastasis;
vi) improving in overall health or well-being of the subject; and/or
vii) decreasing the risk of developing pathology, e.g. metastatic cancer.
The specification fails to disclose a working example of administering via the enormous genus of anatomically distinct routes [parameter 4] a pharmaceutical composition comprising just one(!) leukocyte in combination with just one(!) myxomavirus (Claim 35) [parameter 2, parameter 3] in a method of treating the enormous genus of about 1x10^6 human and non-human animal subject [parameter 1] suffering from the enormous genus of etiologically and pathologically distinct hematological cancers [parameter 5] so as to necessarily and predictably achieve a real-world and clinically meaningful therapeutic result [parameter 6], including, but not limited to:
i) reducing, essentially reducing, or eliminating refractory and drug-resistant Multiple Mylemoma;
ii) producing a desired or beneficial effect;
iii) delaying or inhibiting the development of the disease or condition, delaying or inhibiting the progression of the disease or condition;
iv) ameliorating any observable beneficial effect, a sign or symptom of the disease or pathological condition after it has begun to develop;
v) reducing in severity one or more clinical symptoms;
vi) slowing progression of disease, including metastasis;
vi) improving in overall health or well-being of the subject; and/or
vii) decreasing the risk of developing pathology, e.g. metastatic cancer.
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. See AbbVie 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.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “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)
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
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. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
Without a correlation between structure and function, the claim does 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’).
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that:
the initial myxomavirus encodes and expresses the anti-CD138, anti-CD16 BiKE molecule of SEQ ID NO:4 does not tell you anything at all about the structure/method step/therapeutic result nexus of:
a) the enormous genus of structurally and functionally undisclosed pharmaceutical compositions [parameter 2];
b) the enormous genus of structurally undisclosed dosages of said pharmaceutical compositions, respectively, [parameter 3];
c) the enormous genus of anatomically distinct routes [parameter 4] by which said enormous genus of structurally and functionally undisclosed pharmaceutical compositions, and dosages thereof, are to be administered to…;
d) the enormous genus of about 1x10^6 human and non-human animal subject [parameter 1]; and
e) said enormous genus of about 1x10^6 human and non-human animal subjects suffering from the enormous genus of etiologically and pathologically distinct hematological cancers [parameter 5],
so as to necessarily and predictably achieve a real-world and clinically meaningful therapeutic result [parameter 6], including, but not limited to:
i) reducing, essentially reducing, or eliminating refractory and drug-resistant Multiple Mylemoma;
ii) producing a desired or beneficial effect;
iii) delaying or inhibiting the development of the disease or condition, delaying or inhibiting the progression of the disease or condition;
iv) ameliorating any observable beneficial effect, a sign or symptom of the disease or pathological condition after it has begun to develop;
v) reducing in severity one or more clinical symptoms;
vi) slowing progression of disease, including metastasis;
vi) improving in overall health or well-being of the subject; and/or
vii) decreasing the risk of developing pathology, e.g. metastatic cancer.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that Applicant seeks to claim for themselves:
a) an enormous genus of structurally and functionally undisclosed pharmaceutical compositions [parameter 2];
b) an enormous genus of structurally undisclosed dosages of said pharmaceutical compositions, respectively, [parameter 3];
c) an enormous genus of anatomically distinct routes [parameter 4] by which said enormous genus of structurally and functionally undisclosed pharmaceutical compositions, and dosages thereof, are to be administered to…;
d) an enormous genus of about 1x10^6 human and non-human animal subject [parameter 1]; and
e) said enormous genus of about 1x10^6 human and non-human animal subjects suffering from the enormous genus of etiologically and pathologically distinct hematological cancers [parameter 5], and
f) a broad genus of phenotypic results, many of which are arbitrary and subjective, [parameter 6], including, but not limited to:
i) reducing, essentially reducing, or eliminating refractory and drug-resistant Multiple Mylemoma;
ii) producing a desired or beneficial effect;
iii) delaying or inhibiting the development of the disease or condition, delaying or inhibiting the progression of the disease or condition;
iv) ameliorating any observable beneficial effect, a sign or symptom of the disease or pathological condition after it has begun to develop;
v) reducing in severity one or more clinical symptoms;
vi) slowing progression of disease, including metastasis;
vi) improving in overall health or well-being of the subject; and/or
vii) decreasing the risk of developing pathology, e.g. metastatic cancer.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, enablement rejection.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
10. Claims 30 and 35 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.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, and 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejections.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention. If not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d 731, 737, 8 USPQ2ds 1400, 1404 (Fed. Cir. 1988)). Furthermore, USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
The Quantity of Any Necessary Experimentation to Make or Use the Invention
It is generally recognized in the art that biological compounds often react unpredictably under different circumstances (Nationwide Chem. Corp. v. Wright, 458 F. supp. 828, 839, 192 USPQ95, 105(M.D. Fla. 1976); Affd 584 F.2d 714, 200 USPQ257 (5th Cir. 1978); In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970)). The relative skill of the artisan and the unpredictability of the pharmaceutical art are very high. Where the physiological activity of a chemical or biological compound is considered to be an unpredictable art (Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved" (See In re Fischer, 427 F.2d 833, 839, 166 USPQ 10, 24(CCPA 1970))).
Reliance on animal models is not predictive of clinical outcome. This has been complicated by the inability to extrapolate delivery methods in animals with those in humans or higher animals.
Mingozzi and High (Immune responses to AAV vectors: overcoming barriers to successful gene therapy, Blood 122(1): 23-36, 2013) demonstrate that the human findings are not recapitulated from the animal studies (page 26, col 2, “it seemed logical that one could model the human immune response in these animals, but multiple attempts to do so have also failed”). Hence, lessons learned from small animals such as the mice studies could not recapitulate the ability to deliver adequately in humans.
Kattenhorn et al (Adeno-Associated Virus Gene Therapy for Liver Disease, Human Gene Therapy 27(12): 947-961, November 28, 2016) taught concerns for translation lead to extensive analysis of the effects on clinical use. The use of AAV after initial promising results went on hiatus (pg 947, col. 2, “clinical hiatus in the field”) as the animal models were deficient (pg 953, col. 2, “Although animal models predicted many aspects of the human immune response…, they largely failed to predict responses to AAV capsid”; “Work done in nonhuman primates has not met with any additional success”). This emphasizes that the challenge in humans is to maintain the efficiency of delivery and expression while minimizing any pathogenicity of the virus from which the vector was derived. Eventually, the use of AAV is serotype-dependent (e.g. pg 950, col. 1), organ and concentration dependent. The inability to develop an adequate means of overcoming humoral responses, neutralizing antibody, inactivation of transgene expression, shedding and refractory cells limits the successful means by which the nucleic acid can be administered.
The courts have stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in patent application. 27 USPQ2d 1662 Exparte Maizel. In the instant case, in view of the lack of guidance, working examples, breadth of the claims, the level of skill in the art and state of the art at the time of the claimed invention was made, it would have required undue experimentation to make and/or use the invention as claimed.
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) ("Nascent technology, however, must be enabled with a 'specific and useful teaching.' The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee's instruction. Thus, the public's end of the bargain struck by the patent system is a full enabling disclosure of the claimed technology." (citations omitted)).
As In re Gardner, Roe and Willey, 427 F.2d 786,789 (C.C.P.A. 1970), the skilled artisan might eventually find out how to use the invention after “a great deal of work”. In the case of In re Gardner, Roe and Willey, the invention was a compound which the inventor claimed to have antidepressant activity, but was not enabled because the inventor failed to disclose how to use the invention based on insufficient disclosure of effective drug dosage. The court held that “the law requires that the disclosure in the application shall inform them how to use, not how to find out how to use for themselves”.
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that:
the initial myxomavirus encodes and expresses the anti-CD138, anti-CD16 BiKE molecule of SEQ ID NO:4 does not tell you anything at all about the structure/method step/therapeutic result nexus of:
a) the enormous genus of structurally and functionally undisclosed pharmaceutical compositions [parameter 2];
b) the enormous genus of structurally undisclosed dosages of said pharmaceutical compositions, respectively, [parameter 3];
c) the enormous genus of anatomically distinct routes [parameter 4] by which said enormous genus of structurally and functionally undisclosed pharmaceutical compositions, and dosages thereof, are to be administered to…;
d) the enormous genus of about 1x10^6 human and non-human animal subject [parameter 1]; and
e) said enormous genus of about 1x10^6 human and non-human animal subjects suffering from the enormous genus of etiologically and pathologically distinct hematological cancers [parameter 5],
so as to necessarily and predictably achieve a real-world and clinically meaningful therapeutic result [parameter 6], including, but not limited to:
i) reducing, essentially reducing, or eliminating refractory and drug-resistant Multiple Mylemoma;
ii) producing a desired or beneficial effect;
iii) delaying or inhibiting the development of the disease or condition, delaying or inhibiting the progression of the disease or condition;
iv) ameliorating any observable beneficial effect, a sign or symptom of the disease or pathological condition after it has begun to develop;
v) reducing in severity one or more clinical symptoms;
vi) slowing progression of disease, including metastasis;
vi) improving in overall health or well-being of the subject; and/or
vii) decreasing the risk of developing pathology, e.g. metastatic cancer.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that Applicant seeks to claim for themselves:
a) an enormous genus of structurally and functionally undisclosed pharmaceutical compositions [parameter 2];
b) an enormous genus of structurally undisclosed dosages of said pharmaceutical compositions, respectively, [parameter 3];
c) an enormous genus of anatomically distinct routes [parameter 4] by which said enormous genus of structurally and functionally undisclosed pharmaceutical compositions, and dosages thereof, are to be administered to…;
d) an enormous genus of about 1x10^6 human and non-human animal subject [parameter 1]; and
e) said enormous genus of about 1x10^6 human and non-human animal subjects suffering from the enormous genus of etiologically and pathologically distinct hematological cancers [parameter 5], and
f) a broad genus of phenotypic results, many of which are arbitrary and subjective, [parameter 6], including, but not limited to:
i) reducing, essentially reducing, or eliminating refractory and drug-resistant Multiple Mylemoma;
ii) producing a desired or beneficial effect;
iii) delaying or inhibiting the development of the disease or condition, delaying or inhibiting the progression of the disease or condition;
iv) ameliorating any observable beneficial effect, a sign or symptom of the disease or pathological condition after it has begun to develop;
v) reducing in severity one or more clinical symptoms;
vi) slowing progression of disease, including metastasis;
vi) improving in overall health or well-being of the subject; and/or
vii) decreasing the risk of developing pathology, e.g. metastatic cancer.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Maeda et al (Analyses of repeated failures in cancer therapy for solid tumors: poor tumor-selective drug delivery, low therapeutic efficacy and unsustainable costs, Clinical and Translational Medicine 7: e11, 20 pages, doi.org/10.1186/s40169-018-0185-6; available online March 1, 2018) is considered relevant prior art for having taught that recent immunotherapy for solid tumors (e.g. ovarian cancer) produced outcome failure-rates of 90% (Abstract). Despite the initial enthusiasm for site-specific cancer, the outcomes are bleak and disappointing. Such alarming records of failure of clinical outcomes, the increased publicity for specific vaccines, along with increasing rise of cancer incidence and death created huge and unsustainable cost to the public around the globe. Other recently published articles on basic research and clinical studies of cancer and pathogen-specific vaccines have raised serious concerns about the worthiness, hidden agenda and high costs of these reductionist approaches to such projects that are toxic and repeatedly failed the public (pg 2, col. 1).
While the isolated molecular entities (e.g. ERV-K-gag, ERV-K-env, hFOLR1) are parts of the highly heterogeneous and chaotic landscape in cancer biology, they should not be considered as ‘target’ for therapy as they have little/no value on their own for translational purposes although they may work in mouse models for the selected conditions and duration of therapy which do not apply to human (e.g. pg 2, col’s 1-2, joining para).
The decision makers of such expensive, out-of-focus and fuzzy undertakings seldom consider the life-threatening consequences of wrong and reductionist approaches to drug development for patients and the tremendous economic burden to the society. The irresponsible decision makers of such undertakings, either abandon data on failed outcomes or downplay and ignore the serious consequences of drugs (pg 2, col. 2).
Recent attempts on extensive trials of cancer vaccines, using viral structures or substructures against several cancers such as cervices, prostate, lung, pancreatic and skin also failed to produce the overall protective clinical outcomes. While the prophylactic vaccinations could be the most effective and rational medical preventive strategies, their systemic immunity and effectiveness against cancer is debatable. The elaborate epitopic targets of cancer seem to have limited prospects and therapeutic cancer vaccination is an area of questionable efficacy for immunotherapy and safety (pg 3, col. 2).
As recently reported, a closer look at cancer science reveals that highly powered structure (hierarchy) in cancer/medical establishment (system) versus antisystem and chaotic approaches to cancer research and therapy (‘medical/scientific ponzi schemes’) are potent recipes for failed therapeutics that kills patients but generates huge corporate profit (pg 4, col. 1). Carrying out such reductionist studies under the different name of immunotherapy present the same narrow views of cancer biology and are far from being effective for cancer patients. In these studies, little considerations are given to the cellular immune composition of site-specific tissues, the immune-non-immune local or systemic compensatory response mechanisms, the bioenergetics and oxido redox profiles of tissues toward checkpoint inhibition, as well as, the host immune and non-immune interactions with recruited cells and the adverse responses that are observed following therapy (pg 4, col. 1).
Targeting genetic mutations in site-specific solid cancers that produced repeatedly failed outcomes while generated huge corporate profits. Molecular target drugs created great business motives for drug industry to focus on them in the last six decades. After revealing extremely high incidence of mutations in solid cancer, very little scientific rationale has been presented for developing such costly molecular target drugs that are based on identification of too many evolving genetic mutations in the chaotic cancer environments (pg 5, col. 2). Ovarian cancers may comprise as many as 30-60 different mutations (Table 1).
Evaluation of some drug encapsulated liposomes and micellar nanoparticles reveal another example of failed attempts in cancer chemotherapy. Nanotechnology-based nanomedicine has been the focus of great attention in the past couple of decades. Initially, liposome particles presented the poorest outcomes in the pharmacokinetics because of little considerations of the rapid clearance and removal of nanoparticles by phagocytic cells (pg 9, col. 2).
The major concerns on drug screening are safety and therapeutic efficacies, as well as ethical and financial considerations of decision makers who apply the results that are produced in small animal models in clinical trials to test various anticancer agents in patients which repeatedly failed (pg 10, col. 2).
Prohibitive costs of cancer therapy with repeatedly failed outcomes. Economic impact on medical insurance, and unbearable burden to the society. A serious problem in current cancer chemotherapy involves the cost of care for cancer patients, particularly the astronomical costs of recently claimed molecular ‘targeted’ drug, ‘personalized’ or ‘precision’ medicine with outcome failure rates of 85–95%. While majority of such drugs produced no reasonable benefit to meaningfully extend survival of cancer patients, particularly those with solid tumors, they are tremendously costly for the patients, their families and the public (pg 13).
Concerned voices of independent and competent professionals, oncologists and scientists that are raised for seeking the truth in cancer science, on behalf of the cancer-stricken public for changing the directions in cancer research or therapy or safety and unethical motives behind development of pathogen-specific vaccines (e.g., HPV, flu, meningitis) that repeatedly failed cannot be ignored or silenced any longer by policy/decision makers. We also suggested that the USA policy makers and medical/cancer establishment to return to ‘common sense’ that our forefathers used to serve the public (pg 14, col. 1).
Perrin (Make Mouse Studies Work, Nature (507): 423-425, 2014) taught that the series of clinical trials for a potential therapy can cost hundreds of millions of dollars. The human costs are even greater (pg 423, col. 1). For example, while 12 clinical trials were tested for the treatment of ALS, all but one failed in the clinic (pg 423, col. 2). Experiments necessary in preclinical animal models to characterize new drugs or therapeutic compounds are expensive, time-consuming, and will not, in themselves, lead to new treatments. But without this upfront investment, financial resources for clinical trials are being wasted and [human] lives are being lost (pg 424, col. 1). Animal models are highly variable, and require a large number of animals per test group. Before assessing a drug’s efficacy, researchers should investigate what dose animals can tolerate, whether the drug reaches the relevant tissue at the required dose and how quickly the drug is metabolized or degraded by the body. We estimate that it takes about $30,000 and 6–9 months to characterize the toxicity of a molecule and assess whether enough reaches the relevant tissue and has a sufficient half-life at the target to be potentially effective. If those results are promising, then experiments to test whether a drug can extend an animal’s survival are warranted — this will cost about $100,000 per dose and take around 12 months. At least three doses of the molecule should be tested; this will help to establish that any drug responses are real and suggest what a reasonable dosing level might be. Thus, even assuming the model has been adequately characterized, an investment of $330,000 is necessary just to determine whether a single drug has reasonable potential to treat disease in humans. It could take thousands of patients, several years and hundreds of millions of dollars to move a drug through the clinical development process. The investment required in time and funds is far beyond what any one lab should be expected to do. (pg 425, col.s 2-3). The human costs are even greater: patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment. Clinical trials typically require patients to commit to year or more of treatment, during which they are precluded from pursuing other experimental options (pg 423, col.2 1-3).
Greenberg (Gene Therapy for heart failure, Trends in Cardiovascular Medicine 27: 216-222, 2017) is considered relevant prior art for taught that despite success in experimental animal models, translating gene transfer strategies from the laboratory to the clinic remains at an early stage (Abstract). The success of gene therapy depends on a variety of factors that will ultimately determine the level of transgene expression within the targeted cells. These factors include the vector used for delivery, the method and conditions of delivery of the vector to the [target tissue], the dose that is given and interactions between the host and the vector that alter the efficiency of transfection of [target] cells (e.g. pg 217, col. 1). Failure of therapeutic results may arise because the vector DNA levels were at the lower end of the threshold for dose-response curves in pharmacology studies, and/or only a small proportion of target cells were expressing the therapeutic transgene (e.g. pg 220, col. 1). Although the use of AAVs for gene therapy is appealing, additional information about the best strain of AAVs to use in human patients is needed. Experience indicates that there is a need to carefully consider the dose of the gene therapy vector; however, this has proved to be difficult in early phase developmental studies due to the complexity and cost of such studies (e.g. pg 221, col. 1).
Maguire et al (Viral vectors for gene delivery to the inner ear, Hearing Research 394: e107927, 13 pages, doi.org/10.1016/j.heares.2020.107927, 2020) is considered relevant post-filing art for taught that despite the progress with AAV vectors in the inner ear, little is known regarding the mechanism of transduction of specific cells by AAV within the cochlea (e.g. pg 2, col. 2). There are limitations to what experiments in mice can tell us about the true translation potential of a new therapeutic (e.g. pg 8, col. 2), e.g. species-related physiological differences between mice and humans (e.g. pg 9, col. 1). The AAV dosage is a significant factor in achieving transduction of the target cell, as insufficient dosage may achieve no transduction of the target cells (e.g. pg 9, col. 2).
Tobias (Mouse Study Used in Research, Multiple Sclerosis News Today, multiplesclerosisnewstoday.com/news-posts/2023/09/08/lets-not-get-overexcited-about-any-mice-study-used-research/; September 8, 2023) is considered relevant art for having taught that, “Mice exaggerate and monkeys lie, some researchers jokingly say. (Or is it the other way around?)” The odds of an experimental treatment making it from mouse or monkey to human are very low. Less than 8% of cancer treatments make it from animal studies into a clinical setting, where they’re tested on people, and only 10% of the medications in those clinical trials make it through to government approval. No wonder some researchers joke about mice and monkeys lying and exaggerating.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for enablement under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Claim Rejections - 35 USC § 103
11. The prior rejection of Claim(s) 1, 3, 9, and 11 under AIA 35 U.S.C. 103 as being unpatentable over Song (WO 18/049248; of record) in view of Kang et al (U.S. 2018/0021378; published January 25, 2018; of record), Morrison (U.S. 2016/0115239), Chaudhary (U.S. 2021/0137977; priority to June 1, 2018), and Johnson et al (U.S. 2010/0174053; of record) is withdrawn in light of Applicant’s amendment to Claim 1 to recite wherein the BiKE comprises SEQ ID NO:4.
Double Patenting
12. The prior provisional rejection of Claims 1, 3, 9, and 14 on the ground of nonstatutory double patenting as being unpatentable over claims 120-125 and 132-139 of copending Application No. 17/274051 (reference application; claim set filed August 22, 2025; Notice of Allowance mailed November 4, 2025) is withdrawn in light of Applicant’s filing of a Terminal Disclaimer.
Terminal Disclaimer
13. The terminal disclaimer filed on March 17, 2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of Application No. 17/274051 (Notice of Allowance mailed November 4, 2025), now U.S. Patent 12,569,526 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Citation of Relevant Prior Art
14. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
SEQ ID NO’s:10-12 are disclosed to be anti-CD138 HCDR1-3 motifs, respectively (pg 25 Table).
SEQ ID NO’s:13-15 are disclosed to be anti-CD138 LCDR1-3 motifs, respectively (pg 25 Table).
Dumitru et al (U.S. 2019/0016822; published January 17, 2019; of record) is considered relevant prior art for having disclosed an anti-CD138 polypeptide, SEQ ID NO:212 (indatuximab ravtansine VH region), which is 100% identical to amino acids 144-265 of instant SEQ ID NO:4 and comprises SEQ ID NO’s: 10, 11, and 12, as shown below:
QVQLQQSGSELMMPGASVKISCKATGYTFSNYWIEWVKQRPGHGLEWIGEILPGTGRTIY
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
QVQLQQSGSELMMPGASVKISCKATGYTFSNYWIEWVKQRPGHGLEWIGEILPGTGRTIY
NEKFKGKATFTADISSNTVQMQLSSLTSEDSAVYYCARRDYYGNFYYAMDYWGQGTSVTV
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
NEKFKGKATFTADISSNTVQMQLSSLTSEDSAVYYCARRDYYGNFYYAMDYWGQGTSVTV
SS
||
SS
Dumitru et al also disclosed an anti-CD138 polypeptide, SEQ ID NO:211 (indatuximab ravtansine VL region), that is 100% identical to amino acids 21-127 of instant SEQ ID NO:4 and comprises the CDR motifs of instant SEQ ID NO:13, 14, and 15, as shown below:
DIQMTQSTSSLSASLGDRVTISCSASQGINNYLNWYQQKPDGTVELLIYYTSTLQSGVPS
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
DIQMTQSTSSLSASLGDRVTISCSASQGINNYLNWYQQKPDGTVELLIYYTSTLQSGVPS
RFSGSGSGTDYSLTISNLEPEDIGTYYCQQYSKLPRTFGGGTKLEIK
|||||||||||||||||||||||||||||||||||||||||||||||
RFSGSGSGTDYSLTISNLEPEDIGTYYCQQYSKLPRTFGGGTKLEIK
While Dumitru et al disclosed the antibody may be present in a bispecific antibody or bi-specific T cell engager molecule (e.g. [0003, 567, 579]), Dumitru et al do not disclose the bispecific antibody or bi-specific T cell engager molecule to comprise an anti-CD16 binding domain.
SEQ ID NO’s:16-18 are disclosed to be anti-CD16 HCDR1-3 motifs, respectively (pg 25 Table).
SEQ ID NO’s:19-21 are disclosed to be anti-CD16 LCDR1-3 motifs, respectively (pg 25 Table).
Svendsen et al (U.S. 2008/0299137; of record) is considered relevant prior art for having disclosed fusion proteins, including bi-specific antibodies (e.g. [0003, 243]) comprising an anti-CD16 heavy chain variable region, SEQ ID NO:15, that is 100% identical to amino acids 276-393 of instant SEQ ID NO:4 and comprises the CDR motifs of instant SEQ ID NO:16, 17, and 18, as shown below:
QVTLKESGPGILQPSQTLSLTCSFSGFSLRTSGMGVGWIRQPSGKGLEWLAHIWWDDDKR
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
QVTLKESGPGILQPSQTLSLTCSFSGFSLRTSGMGVGWIRQPSGKGLEWLAHIWWDDDKR
YNPALKSRLTISKDTSSNQVFLKIASVDTADTATYYCAQINPAWFAYWGQGTLVTVSA
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
YNPALKSRLTISKDTSSNQVFLKIASVDTADTATYYCAQINPAWFAYWGQGTLVTVSA
Svendsen et al also disclosed an anti-CD16 light chain variable region, SEQ ID NO:14, that is 89% identical to amino acids 405-519 of instant SEQ ID NO:4 and comprises the CDR motifs substantially similar to instant SEQ ID NO:19, 20, and 21, as shown below:
GGGSDTVLTQSPASLAVSLGQRATISCKASQSVDFDGDSFMNWYQQKPGQPPKLLIYTTS
| ||||| |||||||||| ||||||||| ||||||||||||| ||| ||||||||||
GSTGDTVLT-SPASLAVSLG-RATISCKAS-SVDFDGDSFMNWY--KPG-PPKLLIYTTS
NLESGIPARFSASGSGTDFTLNIHPVEEEDTATYYCQQSNEDPYTFGGGTKLEIK
|||||||||||||||||||||||||||||||||||| ||||||||| |||||||
NLESGIPARFSASGSGTDFTLNIHPVEEEDTATYYC-QSNEDPYTF--GTKLEIK
Svendsen et al do not disclose the bi-specific protein to comprise an anti-CD138 binding domain.
Conclusion
15. Claim 1 is allowed.
Claims 14, 30, and 35 are rejected.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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