Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Detailed Action
This action is in response to the papers filed July 24, 2025.
Amendments
Applicant's response and amendments, filed July 24, 2025, to the prior Office Action is acknowledged. Applicant has cancelled Claims 2-5, 9, and 16-18, amended Claims 1, 6-8, 10-15, and 19-20, and added new claims, Claim 24.
Claims 1, 6-8, 10-15, and 19-24 are pending and under examination.
Priority
This application is a continuation of application 14/468,106 filed on August 25, 2014, now abandoned, which is a continuation in part of:
PCT/US13/050563 filed July 15, 2013;
PCT/US13/051899 filed July 24, 2013;
PCT/US13/055015 filed August 14, 2013;
PCT/US14/17515 filed February 20, 2014; and
PCT/US14/50773 filed August 12, 2014.
Applicant’s claim for the benefit of prior-filed application provisional applications:
61/767,206 filed February 20, 2013;
61/768,992 filed February 25, 2013;
61/774,558 filed March 7, 2013;
61/837,560 filed June 20, 2013;
61/865,092 filed August 12, 2013;
61/894,365 filed October 22, 2013;
61/901,343 filed November 7, 2013;
61/925,190 filed January 8, 2014;
61/925,601 filed January 9, 2014; and
61/938,051 filed February 10, 2014,
under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
With respect to Claims 1, 15, and 19-20, the disclosures of the prior-filed applications 61/767,206 filed February 20, 2013, 61/768,992 filed February 25, 2013, 61/774,558 filed March 7, 2013, 61/837,560 filed June 20, 2013, 61/865,092 filed August 12, 2013, 61/894,365 filed October 22, 2013, 61/901,343 filed November 7, 2013, 61/925,190 filed January 8, 2014, 61/925,601 filed January 9, 2014, 61/938,051 filed February 10, 2014, PCT/US13/050563 field July 15, 2013, PCT/US13/051899 filed July 24, 2013, PCT/US13/055015 filed August 14, 2013, and PCT/US14/017515, filed February 20, 2014 fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The applications do not disclose the step of generating, engrafting, implanting, or injecting cancer cells in a non-human mammal, whereby the cancer cells are treated with an agent before, after, or both before and after, having been generated, engrafted, implanted, or injected in the non-human mammal, wherein the has the functional property(ies) to maintain stem cells in the naive state or revert primed stem cells to the naive state.
While the specification of PCT/US14/017515, filed February 20, 2014, discloses contacting human tumor cells with NME1 dimers or NME7 monomers prior to injecting the cells into a test mammal [0033], ‘515 does not disclose that the NME7 monomers have the instantly recited functional properties, nor that the NME1 dimers or NME7 monomers are contacted with the tumor cells before and/or before and after generating, engrafting, implanting, or injecting tumors in the non-human mammal.
Rather, support for the instant recitations may be found in PCT/US14/050773, filed August 12, 2014, disclosing the steps of implanting a human tumor in a non-human mammal, and contacting the tumors, before, after, or both before and after, with an agent having the functional limitations [0015].
Accordingly, the effective priority date of Claims 1, 15, and 19-20 is granted as August 12, 2014.
If applicant believes the earlier applications provide support for this disclosure, applicant should point out such support with particularity by page and line number in the reply to this Action.
With respect to Claims 1, 15, and 19, the disclosures of the prior-filed applications 61/767,206 filed February 20, 2013, 61/768,992 filed February 25, 2013, 61/774,558 filed March 7, 2013, 61/837,560 filed June 20, 2013, PCT/US13/050563 field July 15, 2013, PCT/US13/051899 filed July 24, 2013, 61/865,092 filed August 12, 2013, PCT/US13/055015 filed August 14, 2013, 61/894,365 filed October 22, 2013, 61/901,343 filed November 7, 2013, and 61/938,051 filed February 10, 2014 fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The applications do not disclose the step of contacting the cancer cells with the 2i or 5i agents.
While 61/925,190 filed January 8, 2014 [00110], 61/925,601 filed January 9, 2014 [00100], and PCT/US14/17515 filed February 20, 2014 [00116] disclose 2i inhibitors, said applications do not disclose “5i” agents.
Rather, support for 5i inhibitors may be found in PCT/US14/50773 filed August 12, 2014 [0012, 300] in reference to Theunissen et al (2014).
Accordingly, the effective priority date of Claims 1, 15, and 19 is granted as August 12, 2014.
If applicant believes the earlier applications provide support for this disclosure, applicant should point out such support with particularity by page and line number in the reply to this Action.
Claim Objections
1. The prior objection to Claims 1, 15, and 19 is withdrawn in light of Applicant’s amendments to the claims.
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.
2. Claims 1, 6-8, 10-15, and 19-24 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.
Claims 1, 15, and 19 recite the limitation wherein the agent that maintains stem cells in the naïve state or reverts primed stem cells to the naïve state is an NME protein that dimerizes MUC1*, e.g., wherein the NME protein that dimerizes MUC1* is an NME1 dimer.
There is a lack of adequate written description regarding the nexus of the enormous genus of structurally and functionally undisclosed NME proteins, including NME1, (parameter 1, structure) having the functional properties of maintaining stem cells in a native state or reverts primed stem cells to the naïve state (parameter 2, function), dimerizing (parameter 3, function), and their corresponding pharmacokinetic properties, respectively, to necessarily and predictably dimerize MUC1* (parameter 4, function).
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).
The claims encompass an enormous genus of structurally and functionally undisclosed NM23 proteins, including NME1, (parameter 1, structure) having the functional properties of maintaining stem cells in a native state or reverts primed stem cells to the naïve state (parameter 2, function), dimerizing (parameter 3, function), and their corresponding pharmacokinetic properties, respectively, to necessarily and predictably dimerize MUC1* (parameter 4, function).
Either any and all NME proteins, including any and all NME1 proteins, have the functional properties of:
maintaining stem cells in a native state or reverts primed stem cells to the naïve state;
dimerizing; and
dimerizing MUC1*, or they do not, and something must change.
The claims denote that not all NME proteins, including not all NME1 proteins, have the functional properties of:
maintaining stem cells in a native state or reverts primed stem cells to the naïve state;
dimerizing; and/or
dimerizing MUC1*.
The specification discloses the NM23 protein need only have at least 30% identity to a reference NM23 protein, e.g. NME1 [00361], which is SEQ ID NO:15.
SEQ ID NO:15 is 177 amino acids in length.
Thus, the claims reasonably encompass as many as 124 amino acid substitutions, insertions, or deletions in SEQ ID NO:15 (30% identity), which is about 2x10^161 possible variants of an NM23 molecule having 30% sequence identity to the amino acid sequence of SEQ ID NO: 15.
(https://www.calculator.net/exponent-calculator.html; last visited July 2, 2024)
Moreira et al (Hot spots—A review of the protein–protein interface determinant amino-acid residues, Proteins 68: 803-812, 2007) is considered relevant prior art for having taught Protein–protein interactions are very complex and can be characterized by their size,
shape, and surface complementarity (e.g. pg 803, Protein-Protein). The hydrophobic and electrostatic interactions they establish, as well as the flexibility of the molecules involved, are very significant.
Moreira et al taught that in a protein–protein interface, a small subset of the buried amino acids typically contribute to the majority of binding affinity as determined by the change in the free energy of binding. Although there is no purely geometric reason, these energetic determinants are compact, centralized regions of residues crucial for protein association (e.g. pg 804, col. 2).
Moreira et al taught that most interfaces are optimal tight-fitting regions characterized by complementary pockets scattered through the central region of the interface, and enriched in structurally conserved residues. These pockets are classified as ‘‘complementary’’ because there is a large complementarity both in shape and in the juxtaposition of hydrophobic and hydrophilic hot spots, with buried charged residues forming salt bridges and hydrophobic residues from one surface fitting into small nooks on the opposite face. Usually, the hot spot of one face packs against the hot spot of the other face establishing a region determinant for complex binding (e.g. pg 806, col. 1). Complementarity is basically affected by the size of the buried surface, alignment of polar and nonpolar residues, number of buried waters, and the packing densities of atoms involved in the protein–protein interface. Packing defects at the protein–protein interface result in these gaps or pockets, and it is unclear whether unfilled pockets contain water molecules or how the dynamics of water molecules entering and escaping these pockets may affect binding stability (e.g. pg 807, col. 2). Moreira et al taught that common methodology to determine hot spot locations on the artisan’s protein of interest, alanine-scanning mutagenesis is slow and labor-intensive (e.g. pg 804, col. 1). Similarly, systematic mutagenesis is very laborious and time-consuming to perform, as individual mutant proteins must be purified and analyzed separately (e.g. pg 808, col. 2).
Ng et al (Predicting the Effects of Amino Acid Substitutions on Protein Function, Annual Review Genomics Human Genetics 7: 61-80, 2006) is considered relevant prior art for having taught that non-synonymous nucleotide changes which introduce amino acid changes in the corresponding protein have the largest impact on human health. Most algorithms to predict amino acid substation consequences of protein function indicate about 25% to 30% of amino acid changes negatively affect protein function (Abstract). Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to multiple amino acid changes, including insertions or deletions. Ng et al taught that 83% of disease-causing mutations affect protein stability (e.g. pg 63, col. 1), which in this case, would affect the ability of the enormously vast genus of structurally undisclosed NM23 protein variants to bind MUC1*, let alone activate MUC1*. Ng et al taught that while multiple sequence alignment of the homologous sequences reveals what positions have been conserved throughout evolutionary time, and these positions are inferred to be important for function (e.g. pg 63, col. 1), Users should be cautious even with proteins that are judged to be orthologous based on phylogeny. Orthologous genes in different species are derived from a common ancestor, but they may not necessarily have the same function. If function has changed, then amino acids that are important for the function of one protein may not necessarily be important for the function of the ortholog. 2% of disease-causing mutations in human genes are identical to the sequences of their respective mouse orthologs, suggesting that even though these positions have huge phenotypic effects on human health, they have different roles or are no longer important in mice If the orthologs in alignment have slightly different functions, then the positions that differentiate function among orthologs may be incorrectly predicted. (e.g. pg 68, col. 1). When there are many missense mutations in the gene(s) of interest, assaying all missense mutations, which introduce amino acid changes, can be expensive and time-consuming (e.g. pg 74, col. 1). Prediction accuracy has gradually improved, but few head-to-head comparisons exist. Moreover, as the number of servers providing AAS prediction increases, it will become increasingly difficult for investigators to interpret the predictions. (e.g. pg 74, col. 2). Ng et al taught that the error rate of functional annotations in the sequence database is considerable, making it even more difficult to infer correct function from a structural comparison of a new sequence with a sequence database (e.g. Table 1, error rates of about 40% to 60%).
Prediction of protein structure by homology and/or algorithm is notoriously difficult, as one of ordinary skill in the art would immediately understand.
Consequently, the gap between the number of as-yet to be discovered NM23 protein variant sequences of the claimed, but not structurally, nor functionally, disclosed, enormously vast genus of NM23 protein variants, is considered to be tremendous, notoriously difficult, slow, very laborious and time-consuming for the ordinary artisans to determine for themselves that which Applicant has failed to disclose.
Therefore, based on the discussions above concerning the specific examples of structurally similar proteins that have different functions, along with the art's recognition that one cannot rely upon structural similarity alone to determine functionality, the specification fails to reasonably inform the ordinary artisan how to make and use the claimed enormously vast genus of structurally and functionally undisclosed NM23 protein variants having the recited biological and functional properties of binding to and activating MUC1*.
Disclosure of putative structures having a theorized function in the absence of experimental data demonstrating the theorized function is insufficient to demonstrate possession of a representative number of species by disclosure of relevant, identifying characteristics (i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics), sufficient to show the applicant was in possession of the claimed invention.
The claims fail to recite and the specification fails to disclose the structure/function nexus between the enormously vast genus of about 2x10^161 possible variants of NM23 molecules having as little as 30% sequence identity to the amino acid sequence of SEQ ID NO: 15 (parameter 1, structure) that will necessarily and predictably achieve maintaining stem cells in a native state or reverts primed stem cells to the naïve state (parameter 2, function), dimerizing (parameter 3, function), and their corresponding pharmacokinetic properties, respectively, to necessarily and predictably dimerize MUC1* (parameter 4, function).
The claims fail to recite, and the specification fails to disclose, a first NM23 protein variant of SEQ ID NO:15 of the enormously vast genus of about 2x10^161 structurally and functionally undisclosed NM23 protein variants that is unable to achieve binding to and activating MUC1*, as opposed to a second NM23 protein variant of SEQ ID NO:15 of the enormously vast genus of about 2x10^161 structurally and functionally undisclosed NM23 protein variants that will necessarily and predictably achieve maintaining stem cells in a native state or reverts primed stem cells to the naïve state (parameter 2, function), dimerizing (parameter 3, function), and their corresponding pharmacokinetic properties, respectively, to necessarily and predictably dimerize MUC1* (parameter 4, function).
The claims fail to recite and the specification fails to disclose how to modify or otherwise transform a first NM23 protein variant of SEQ ID NO:15 of the enormously vast genus of about 2x10^161 structurally and functionally undisclosed NM23 protein variants that is unable to achieve binding to and activating MUC1* into a second NM23 protein variant of SEQ ID NO:15 of the enormously vast genus of about 2x10^161 structurally and functionally undisclosed NM23 protein variants that will necessarily and predictably achieve maintaining stem cells in a native state or reverts primed stem cells to the naïve state (parameter 2, function), dimerizing (parameter 3, function), and their corresponding pharmacokinetic properties, respectively, to necessarily and predictably dimerize MUC1* (parameter 4, function).
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”).
Recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. These claims are usually handled in Technology Center 1600. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen" test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quotingAriad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional. Id. The Amgen decision will be added to the MPEP in due course.
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)
Since the genetic code is widely known, a disclosure of an amino acid sequence would provide sufficient information such that one would accept that an inventor was in possession of the full genus of nucleic acids encoding a given amino acid sequence, but not necessarily any particular species. Cf. In re Bell, 991 F.2d 781, 785, 26 USPQ2d 1529, 1532 (Fed. Cir. 1993) and In re Baird, 16 F.3d 380, 382, 29 USPQ2d 1550, 1552 (Fed. Cir. 1994).
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 NM23 molecule has as little as 30% sequence identity to the amino acid sequence of SEQ ID NO: 15 does not tell you anything at all about the structure (amino acid sequences) of the enormously vast genus of about the enormously vast genus of about 2x10^161 possible variants of NM23 molecules having as little as 30% sequence identity to the amino acid sequence of SEQ ID NO: 15 (parameter 1, structure) that will necessarily and predictably achieve the functional properties of maintaining stem cells in a native state or reverts primed stem cells to the naïve state (parameter 2, function), dimerizing (parameter 3, function), and their corresponding pharmacokinetic properties, respectively, to necessarily and predictably dimerize MUC1* (parameter 4, function).
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 the claimed class of NM23 variant(s) does not include just the NM23 of SEQ ID NO:15, but rather includes an enormously vast genus of about 2x10^161 structurally and functionally undisclosed NM23 protein variants having as little as 30% identity to the amino acid sequence of SEQ ID NO:15.
“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.
The art does not teach, and the specification fails to disclose, NM23 protein variants that are not more than 30% identical to a reference NM23 SEQ ID NO:15 species (parameter 1, structure), nor the corresponding nexus of the biological properties of the enormously vast genus of 2x10^161 structurally and functionally undisclosed NM23 protein variants that would necessarily and predictably achieve the functional properties of maintaining stem cells in a native state or reverts primed stem cells to the naïve state (parameter 2, function), dimerizing (parameter 3, function), and their corresponding pharmacokinetic properties, respectively, to necessarily and predictably dimerize MUC1* (parameter 4, function).
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the enormously vast genus of 2x10^161 structurally and functionally undisclosed NM23 protein variants (parameter 1, structure) that would necessarily and predictably achieve the recited functional properties of maintaining stem cells in a native state or reverts primed stem cells to the naïve state (parameter 2, function), dimerizing (parameter 3, function), and their corresponding pharmacokinetic properties, respectively, to necessarily and predictably dimerize MUC1* (parameter 4, function).
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.
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)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Response to Arguments
Applicant argues that that comma punctuation is not needed to separate elements of a list, per “and” examples, and that the phrase “or an NME protein having greater than 30%...” refers to the NME family member genus, e.g. NME7, not NME1.
Applicant’s argument(s) has been fully considered, but is not persuasive.
In essence, comma usage is key to determining which element, A or B, is being modified by a phrase following "A or B".
When the modifier applies to all nouns in the list, a comma is not needed.
When a modifier follows "A or B" without a comma, it indicates that the modifier applies to both A and B collectively as a restrictive element.
Without a comma, especially when dealing with lists, it can become ambiguous whether the modifier is restrictive (applies to all items in the list or the last item only).
Example of Ambiguity: "The company offers either a flexible schedule or a higher salary that attracts many employees." Does "that attracts many employees" describe both the schedule and the salary, or just the salary?
To avoid ambiguity, it's often best to rephrase the sentence or be more explicit if only one of the items is intended to be modified.
Rephrased for clarity: "The company offers a flexible schedule, or a higher salary, which attracts many employees." (Here, only the higher salary attracts many employees.)
If there's a chance the modifier might be misinterpreted as applying only to the last noun in the list, then using a comma before "or" (an Oxford/serial comma) can improve clarity.
“A, or B” (with a modifier)
When “or” introduces an independent clause, a comma should be placed before it. An independent clause can stand alone as a complete sentence.
See provided Google Search results (“multiple nouns followed by modifier, with “or”, comma”; “modifier following “A or B”, no comma”; google.com/search; last visited August 11, 2025).
Applicant argues that that the phrase “or an NME protein having greater than 30%...” refers to the NME family member genus, not NME1.
Applicant’s argument(s) has been fully considered, but is not persuasive.
As a first matter, [00361] discloses “NME1 or an NME protein having greater than 30%, …”.
[00361] does not disclose “NME1, or an NME protein having greater than 30%, …”.
The phrase “A or B” means one can choose either option A or option B. Thus, the phrase “having greater than 30%,...” is reasonably understood to refer back to both “NME1” (option A) and “an NME protein” (option B).
See, instead, for example, the use commas in Claim 1, “an NMEl dimer, NME7 monomer, NME7-AB, NME6 dimer, or bacterial NME”.
Thus, the specification appears to suffer from ambiguity for want of a comma or semi-colon to avoid the ambiguity that a missing serial comma would otherwise create. See, for example, O'Connor v. Oakhurst Dairy.
As a second matter, as shown below, the art recognizes the term “NME1” to be synonymous with other proteins known in the art by different names.
GenBank NP_001287625.1 (Drosophila melanogaster, AWD, December 2023) provides an insect protein having as little as 77% identity to human NME1. Thus, while it is clear that the insect AWD protein would fulfill Applicant’s argued interpretation of “an NME protein” family member, per [00361], Applicant’s argued interpretation of the metes and bounds of “NME1” is discordant the art-recognized understanding. Rather, it would seem that the metes and bounds of “NME1” would also encompass at little as 77% identity to human NME1.
It is clear that Applicant and/or Applicant’s representative(s) and the Examiner disagree on the issue of whether or not the specification clearly defines the metes and bounds of “NME1”.
The Examiner notes, for example, that [00363] clearly discloses “human NME1 dimers”, and SEQ ID NO:15 [00132]; however, instant claims are broader in scope than the both of human NME1 dimers and SEQ ID NO:15 (which is the human NME1 amino acid sequence).
Appropriate correction and/or clarification is required.
See also discussion below per the 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
3. Claims 1, 6-8, 10-15, and 19-24 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for an NM23 protein (syn. NME1, [0042]; [0047], “human NME1/NM23 dimers”; [0051] “recombinant human NM23 dimers”; [0052], “human recombinant NM23, also called NME1, dimers”) having the amino acid sequence of SEQ ID NO:15 that binds to and dimerizes MUC1*,
does not reasonably provide enablement for an enormously vast genus of structurally and functionally undisclosed NM23 proteins that are to have the functional properties of binding to and dimerizing MUC1*. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
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.
Claims 1, 15, and 19 have been amended to recite the limitation wherein the agent that maintains stem cells in the naïve state or reverts primed stem cells to the naïve state is an NME protein that dimerizes MUC1*, e.g., wherein the NME protein that dimerizes MUC1* is an NME1 dimer.
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).
The claims encompass an enormous genus of structurally and functionally undisclosed NM23 proteins, including NME1, (parameter 1, structure) having the functional properties of maintaining stem cells in a native state or reverts primed stem cells to the naïve state (parameter 2, function), dimerizing (parameter 3, function), and their corresponding pharmacokinetic properties, respectively, to necessarily and predictably dimerize MUC1* (parameter 4, function).
Either any and all NME proteins, including any and all NME1 proteins, have the functional properties of:
maintaining stem cells in a native state or reverts primed stem cells to the naïve state;
dimerizing; and
dimerizing MUC1*, or they do not, and something must change.
The claims denote that not all NME proteins, including not all NME1 proteins, have the functional properties of:
maintaining stem cells in a native state or reverts primed stem cells to the naïve state;
dimerizing; and/or
dimerizing MUC1*.
The specification discloses the NM23 protein need only have at least 30% identity to a reference NM23 protein, e.g. NME1 [00361], which is SEQ ID NO:15.
SEQ ID NO:15 is 177 amino acids in l20ength.
Thus, the claims reasonably encompass as many as 124 amino acid substitutions, insertions, or deletions in SEQ ID NO:15 (30% identity), which is about 2x10^161 possible variants of an NM23 molecule having 30% sequence identity to the amino acid sequence of SEQ ID NO: 15.
(https://www.calculator.net/exponent-calculator.html; last visited July 2, 2024)
Moreira et al (Hot spots—A review of the protein–protein interface determinant amino-acid residues, Proteins 68: 803-812, 2007) is considered relevant prior art for having taught Protein–protein interactions are very complex and can be characterized by their size,
shape, and surface complementarity (e.g. pg 803, Protein-Protein). The hydrophobic and electrostatic interactions they establish, as well as the flexibility of the molecules involved, are very significant.
Moreira et al taught that in a protein–protein interface, a small subset of the buried amino acids typically contribute to the majority of binding affinity as determined by the change in the free energy of binding. Although there is no purely geometric reason, these energetic determinants are compact, centralized regions of residues crucial for protein association (e.g. pg 804, col. 2).
Moreira et al taught that most interfaces are optimal tight-fitting regions characterized by complementary pockets scattered through the central region of the interface, and enriched in structurally conserved residues. These pockets are classified as ‘‘complementary’’ because there is a large complementarity both in shape and in the juxtaposition of hydrophobic and hydrophilic hot spots, with buried charged residues forming salt bridges and hydrophobic residues from one surface fitting into small nooks on the opposite face. Usually, the hot spot of one face packs against the hot spot of the other face establishing a region determinant for complex binding (e.g. pg 806, col. 1). Complementarity is basically affected by the size of the buried surface, alignment of polar and nonpolar residues, number of buried waters, and the packing densities of atoms involved in the protein–protein interface. Packing defects at the protein–protein interface result in these gaps or pockets, and it is unclear whether unfilled pockets contain water molecules or how the dynamics of water molecules entering and escaping these pockets may affect binding stability (e.g. pg 807, col. 2). Moreira et al taught that common methodology to determine hot spot locations on the artisan’s protein of interest, alanine-scanning mutagenesis is slow and labor-intensive (e.g. pg 804, col. 1). Similarly, systematic mutagenesis is very laborious and time-consuming to perform, as individual mutant proteins must be purified and analyzed separately (e.g. pg 808, col. 2).
Ng et al (Predicting the Effects of Amino Acid Substitutions on Protein Function, Annual Review Genomics Human Genetics 7: 61-80, 2006) is considered relevant prior art for having taught that non-synonymous nucleotide changes which introduce amino acid changes in the corresponding protein have the largest impact on human health. Most algorithms to predict amino acid substation consequences of protein function indicate about 25% to 30% of amino acid changes negatively affect protein function (Abstract). Existing prediction tools primarily focus on studying the deleterious effects of single amino acid substitutions through examining amino acid conservation at the position of interest among related sequences, an approach that is not directly applicable to multiple amino acid changes, including insertions or deletions. Ng et al taught that 83% of disease-causing mutations affect protein stability (e.g. pg 63, col. 1), which in this case, would affect the ability of the enormously vast genus of structurally undisclosed NM23 protein variants to bind MUC1*, let alone activate MUC1*. Ng et al taught that while multiple sequence alignment of the homologous sequences reveals what positions have been conserved throughout evolutionary time, and these positions are inferred to be important for function (e.g. pg 63, col. 1), Users should be cautious even with proteins that are judged to be orthologous based on phylogeny. Orthologous genes in different species are derived from a common ancestor, but they may not necessarily have the same function. If function has changed, then amino acids that are important for the function of one protein may not necessarily be important for the function of the ortholog. 2% of disease-causing mutations in human genes are identical to the sequences of their respective mouse orthologs, suggesting that even though these positions have huge phenotypic effects on human health, they have different roles or are no longer important in mice If the orthologs in alignment have slightly different functions, then the positions that differentiate function among orthologs may be incorrectly predicted. (e.g. pg 68, col. 1). When there are many missense mutations in the gene(s) of interest, assaying all missense mutations, which introduce amino acid changes, can be expensive and time-consuming (e.g. pg 74, col. 1). Prediction accuracy has gradually improved, but few head-to-head comparisons exist. Moreover, as the number of servers providing AAS prediction increases, it will become increasingly difficult for investigators to interpret the predictions. (e.g. pg 74, col. 2). Ng et al taught that the error rate of functional annotations in the sequence database is considerable, making it even more difficult to infer correct function from a structural comparison of a new sequence with a sequence database (e.g. Table 1, error rates of about 40% to 60%).
Prediction of protein structure by homology and/or algorithm is notoriously difficult, as one of ordinary skill in the art would immediately understand.
Consequently, the gap between the number of as-yet to be discovered NM23 protein variant sequences of the claimed, but not structurally, nor functionally, disclosed, enormously vast genus of NM23 protein variants, is considered to be tremendous, notoriously difficult, slow, very laborious and time-consuming for the ordinary artisans to determine for themselves that which Applicant has failed to disclose.
Therefore, based on the discussions above concerning the specific examples of structurally similar proteins that have different functions, along with the art's recognition that one cannot rely upon structural similarity alone to determine functionality, the specification fails to reasonably inform the ordinary artisan how to make and use the claimed enormously vast genus of structurally and functionally undisclosed NM23 protein variants having the recited biological and functional properties of binding to and activating MUC1*.
Disclosure of putative structures having a theorized function in the absence of experimental data demonstrating the theorized function is insufficient to demonstrate possession of a representative number of species by disclosure of relevant, identifying characteristics (i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics), sufficient to show the applicant was in possession of the claimed invention.
The claims fail to recite and the specification fails to disclose the structure/function nexus between the enormously vast genus of about 2x10^161 possible variants of NM23 molecules having as little as 30% sequence identity to the amino acid sequence of SEQ ID NO: 15 (parameter 1, structure) that will necessarily and predictably achieve maintaining stem cells in a native state or reverts primed stem cells to the naïve state (parameter 2, function), dimerizing (parameter 3, function), and their corresponding pharmacokinetic properties, respectively, to necessarily and predictably dimerize MUC1* (parameter 4, function).
The claims fail to recite, and the specification fails to disclose, a first NM23 protein variant of SEQ ID NO:15 of the enormously vast genus of about 2x10^161 structurally and functionally undisclosed NM23 protein variants that is unable to achieve binding to and activating MUC1*, as opposed to a second NM23 protein variant of SEQ ID NO:15 of the enormously vast genus of about 2x10^161 structurally and functionally undisclosed NM23 protein variants that will necessarily and predictably achieve maintaining stem cells in a native state or reverts primed stem cells to the naïve state (parameter 2, function), dimerizing (parameter 3, function), and their corresponding pharmacokinetic properties, respectively, to necessarily and predictably dimerize MUC1* (parameter 4, function).
The claims fail to recite and the specification fails to disclose how to modify or otherwise transform a first NM23 protein variant of SEQ ID NO:15 of the enormously vast genus of about 2x10^161 structurally and functionally undisclosed NM23 protein variants that is unable to achieve binding to and activating MUC1* into a second NM23 protein variant of SEQ ID NO:15 of the enormously vast genus of about 2x10^161 structurally and functionally undisclosed NM23 protein variants that will necessarily and predictably achieve maintaining stem cells in a native state or reverts primed stem cells to the naïve state (parameter 2, function), dimeriz