DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
1. Claims 1-14 as amended on April 25, 2024 are pending and under consideration.
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.
2. Claims 1-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are drawn to a set of a first and a second precursor protein, wherein each precursor protein comprises two polypeptides that are associated with each other via dimerization domains, wherein at least one of the precursor proteins comprises a moiety selected from a receptor ligand and an enzyme, wherein said moiety is functionally inactive, wherein said moiety is fused to the dimerization domain, wherein upon polypeptide chain exchange between the first and the second precursor protein an activated protein is formed, wherein the activated protein comprises one polypeptide from the first precursor protein and one polypeptides from the second precursor protein, wherein both polypeptides are associated with each other via their dimerization domains, and wherein the activated protein comprises said moiety, characterized in that the activated protein comprises said moiety in functionally active form.
The claims encompass a broad genera of a moiety selected from a receptor ligand and an enzyme, wherein said moiety is functionally inactive, wherein said moiety is fused to a dimerization domain, wherein upon polypeptide chain exchange between the first and the second precursor protein an activated protein is formed.
The state of the art is such that it is well known in the art that protein biochemistry is unpredictable and, thus, predicting protein function from structure is unpredictable. The unpredictable sensitivity of proteins interaction and function to alterations of even a single amino acid in a sequence are exemplified by Coleman et al. (Research in Immunology, 1994; 145(1): 33-36) who teach single amino acid changes in an antigen can effectively abolish antibody antigen binding. Further, the sensitivity of binding proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J of Cell Bio. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein. Pero et al. (US PG Pub 2003/0105000) specifically teach that the SH2 domain of Grb14 is 81% similar to the SH2 domain of Grb7 on the amino acid level, but although Grb7 binds to ErbB2, Grb14 does not bind to ErbB2. Further, although the SH2 domain of Grb2 is only 50% similar to Grb7 on the amino acid level, both Grb2 and Grb7 bind to the same site on ErbB2. See ¶ [0255] of the published application. Furthermore, US 2009/0075313 (Massoud et al. Mar. 19, 2009) teaches that steric hinderance from the dimerization domains can inhibit the activity of linked split proteins (i.e. thymidine kinase) after the split domains are brought together for activation. See ¶¶ [0224-0225] and Fig. 13. These references demonstrate that even a single amino acid alteration or what appears to be an inconsequential chemical modification will often dramatically affect the biological activity and characteristics of a binding protein. Additionally, Ibragimova and Wade (Biophysical Journal, Oct 1999, Vol. 77, pp. 2191-2198) teach that factors affecting protein folding and stability are governed by many small and often opposing effects and that even when the “rules” are known for altering the stability of a protein fold by the introduction of a single point mutation the result is not reliable because the balance of forces governing folding differs for different protein sequences, and that the determination of the relative magnitude of the forces governing the folding and stability of a given protein sequence is not straightforward (page 2191, first column, lines 12-17 and second column, lines 3-8). Thus, given the above, it is clear that in the protein biochemistry arts an adequate written description is essential for one of skill in the art to make and use the claimed invention.
Although drawn to DNA arts, the findings in University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc. are relevant to the instant claims. The Federal Circuit addressed the application of the written description requirement to DNA-related inventions in University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997). The court stated that "[a] written description of an invention involving a chemical genus, like a description of a chemical species, requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Id. At 1567, 43 USPQ2d at 1405. The court also stated that
a generic statement such as "vertebrate insulin cDNA" or "mammalian insulin cDNA" without more, is not an adequate written description of the genus because it does not distinguish the genus from others, except by function. It does not specifically define any of the genes that fall within its definition. It does not define any structural features commonly possessed by members of the genus that distinguish them from others. One skilled in the art therefore cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus. A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is.
Id. At 1568, 43 USPQ2d at 1406. The court concluded that "naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material." Id.
Finally, the court addressed the manner by which a genus of cDNAs might be described. "A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNAs, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus." Id.
The Federal Circuit has recently clarified that a DNA molecule can be adequately described without disclosing its complete structure. See Enzo Biochem, Inc. V. Gen-Probe Inc., 296 F.3d 1316, 63 USPQ2d 1609 (Fed. Cir. 2002). The Enzo court adopted the standard that "the written description requirement can be met by 'show[ing] that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics ... i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. " Id. At 1324, 63 USPQ2d at 1613 (emphasis omitted, bracketed material in original).
The inventions at issue in Lilly and Enzo were DNA constructs per se, the holdings of those cases are also applicable to claims such as those at issue here. Thus, the instant specification may provide an adequate written description of a moiety selected from a receptor ligand and an enzyme, wherein said moiety is functionally inactive, wherein said moiety is fused to the dimerization domain, wherein upon polypeptide chain exchange between the first and the second precursor protein an activated protein is formed, per Lilly by structurally describing a representative number of said moieties, or by describing "structural features common to the members of the genus, which features constitute a substantial portion of the genus." Alternatively, per Enzo, the specification can show that the claimed invention is complete "by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics."
In this case, the specification does not provide an adequate description of a moiety selected from a receptor ligand and an enzyme, wherein said moiety is functionally inactive, wherein said moiety is fused to the dimerization domain, wherein upon polypeptide chain exchange between the first and the second precursor protein an activated protein is formed in a manner that satisfies either the Lilly or Enzo standards.. Although the specification discloses the dimerization activatable ligands IL-2, IL-4, and IL-12 and luciferase enzyme, this does not provide an adequate description of a dimerization activatable ligand or enzyme that would satisfy the standard set out in Enzo because the genera of activatable ligands and enzymes are very large and the structural features of dimerization activatable IL-2, IL-4, and IL-12 and luciferase do not sufficiently provide structure and functional characteristics when coupled with a known correlation between function and structure for the breadth of the claimed genera.
The specification also fails to describe a moiety selected from a receptor ligand and an enzyme, wherein said moiety is functionally inactive, wherein said moiety is fused to the dimerization domain, wherein upon polypeptide chain exchange between the first and the second precursor protein an activated protein is formed by the test set out in Lilly. The specification describes only the dimerization activatable ligands IL-2, IL-4, and IL-12 and luciferase enzyme.
Therefore, it necessarily fails to describe a "representative number" of species of dimerization activatable ligand or enzyme. In addition, the specification also does not describe "structural features common to the members of the genus, which features constitute a substantial portion of the genus."
Thus, the specification does not provide an adequate written description of a moiety selected from a receptor ligand and an enzyme, wherein said moiety is functionally inactive, wherein said moiety is fused to the dimerization domain, wherein upon polypeptide chain exchange between the first and the second precursor protein an activated protein is formed that is required to practice the claimed invention or reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the broadly claimed invention.
3. Claims 1-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a set of a first and a second precursor protein, wherein each precursor protein comprises two polypeptides that are associated with each other via dimerization domains, wherein at least one of the precursor proteins comprises a moiety selected from IL-2, IL-4, IL-12 and luciferase, wherein said moiety is functionally inactive, wherein said moiety is fused to the dimerization domain, wherein upon polypeptide chain exchange between the first and the second precursor protein an activated protein is formed, wherein the activated protein comprises one polypeptide from the first precursor protein and one polypeptides from the second precursor protein, wherein both polypeptides are associated with each other via their dimerization domains, and wherein the activated protein comprises said moiety, characterized in that the activated protein comprises said moiety in functionally active form, wherein the dimerization domains are CH3 domains that have a modified interface to support polypeptide chain exchange between the first and the second precursor protein, does not reasonably provide enablement for a set of a first and a second precursor protein, wherein each precursor protein comprises two polypeptides that are associated with each other via dimerization domains, wherein at least one of the precursor proteins comprises a moiety selected from a receptor ligand and an enzyme, wherein said moiety is functionally inactive, wherein said moiety is fused to the dimerization domain, wherein upon polypeptide chain exchange between the first and the second precursor protein an activated protein is formed, wherein the activated protein comprises one polypeptide from the first precursor protein and one polypeptides from the second precursor protein, wherein both polypeptides are associated with each other via their dimerization domains, and wherein the activated protein comprises said moiety, characterized in that the activated protein comprises said moiety in functionally active form.. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized in In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The court in Wands states: "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
The claims are drawn to a set of a first and a second precursor protein, wherein each precursor protein comprises two polypeptides that are associated with each other via dimerization domains, wherein at least one of the precursor proteins comprises a moiety selected from a receptor ligand and an enzyme, wherein said moiety is functionally inactive, wherein said moiety is fused to the dimerization domain, wherein upon polypeptide chain exchange between the first and the second precursor protein an activated protein is formed, wherein the activated protein comprises one polypeptide from the first precursor protein and one polypeptides from the second precursor protein, wherein both polypeptides are associated with each other via their dimerization domains, and wherein the activated protein comprises said moiety, characterized in that the activated protein comprises said moiety in functionally active form.
The claims encompass a broad genera of a moiety selected from a receptor ligand and an enzyme, wherein said moiety is functionally inactive, wherein said moiety is fused to a dimerization domain, wherein upon polypeptide chain exchange between the first and the second precursor protein an activated protein is formed after polypeptide chain exchange.
The specification teaches dimerization activatable ligands IL-2, IL-4, and IL-12 and luciferase enzyme linked too destabilized “knobs-into-holes” CH3 domains for polypeptide exchange. See Examples 1-10.
One of skill in the art cannot predictably extrapolate the teachings of the specification to enable the scope of the claims because the claims encompass a broad genera of receptor ligand and an enzyme, wherein said moiety is functionally inactive, wherein said moiety is fused to a dimerization domain, wherein upon polypeptide chain exchange between the first and the second precursor protein an activated protein is formed because protein biochemistry is unpredictable and, thus, predicting protein function from structure is unpredictable. The unpredictable sensitivity of proteins interaction and function to alterations of even a single amino acid in a sequence are exemplified by Coleman et al. (Research in Immunology, 1994; 145(1): 33-36) who teach single amino acid changes in an antigen can effectively abolish antibody antigen binding. Further, the sensitivity of binding proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J of Cell Bio. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein. Pero et al. (US PG Pub 2003/0105000) specifically teach that the SH2 domain of Grb14 is 81% similar to the SH2 domain of Grb7 on the amino acid level, but although Grb7 binds to ErbB2, Grb14 does not bind to ErbB2. Further, although the SH2 domain of Grb2 is only 50% similar to Grb7 on the amino acid level, both Grb2 and Grb7 bind to the same site on ErbB2. See ¶ [0255] of the published application. Furthermore, US 2009/0075313 (Massoud et al. Mar. 19, 2009) teaches that steric hinderance from the dimerization domains can inhibit the activity of split proteins (i.e. thymidine kinase) after the split domains are brought together for activation. See ¶¶ [0224-0225] and Fig. 13. These references demonstrate that even a single amino acid alteration or what appears to be an inconsequential chemical modification will often dramatically affect the biological activity and characteristics of a binding protein. Additionally, Ibragimova and Wade (Biophysical Journal, Oct 1999, Vol. 77, pp. 2191-2198) teach that factors affecting protein folding and stability are governed by many small and often opposing effects and that even when the “rules” are known for altering the stability of a protein fold by the introduction of a single point mutation the result is not reliable because the balance of forces governing folding differs for different protein sequences, and that the determination of the relative magnitude of the forces governing the folding and stability of a given protein sequence is not straightforward (page 2191, first column, lines 12-17 and second column, lines 3-8). Thus, given the unpredictability in the art set forth above, it is clear that in the protein biochemistry arts an adequate guidance is essential for one of skill in the art to make and use the broadly claimed invention without undue experimentation. Given the limited examples provided in the specification, a nexus has not been established between the broadly claimed invention and the guidance provided in the specification as filed. Thus, undue experimentation would be required to make and use the invention as claimed.
Closest Prior Art
4. WO 2019/086362 (Brinkmann U. et al. 09 May 2019, IDS) teaches a method for the generation of multispecific antibodies directly on the cell-surface at the site of action by a half-antibody exchange reaction between two 2/3-IgGs or two 2/3-BiFabs destabilized in one half by asymmetric perturbing mutations fostering the generation of correctly assembled full length bi-or multi-specific antibodies. See abstract and entire document.
WO 2020/216879 (Brinkmann U. et al. 29 Oct. 2020, IDS) teaches multispecific polypeptides activated by polypeptide chain exchange. See entire document.
However, the references do not teach or suggest where a precursor protein comprises a moiety selected from a receptor ligand and an enzyme, wherein said moiety is functionally inactive, wherein said moiety is fused to a dimerization domain, wherein upon polypeptide chain exchange between a first and a second precursor protein an activated protein is formed.
Conclusion
6. No claims allowed.
7. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached M-F 8:30-5:30 Eastern Time.
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/PETER J REDDIG/ Primary Examiner, Art Unit 1646