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 .
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-9 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 rejected claims cover compositions comprising: conjugates of a targeting substance and a cytotoxin; and glycosylated chlorin derivatives.
To satisfy the written-description requirement, the specification must describe every element of the claimed invention in sufficient detail so that one of ordinary skill in the art would recognize that the inventor possessed the claimed invention at the time of filing. Vas-Cath, 935 F.3d at 1563; see also Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997) (patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention”); In re Gosteli, 872 F.2d 1008, 1012 (Fed. Cir. 1989) (“the description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed”).
With regard to the recited genus of conjugates and genus of glycosylated chlorin derivatives, the following applies:
Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 94 USPQ2d 1161 (Fed. Cir. 2010) states that “...a generic claim may define the boundaries of a vast genus of chemical compounds...the question may still remain whether the specification, including the original claim language, demonstrates that the applicant invented species sufficient to support a claim to a genus”. See page 1171.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
See also Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996) (a “laundry list” disclosure of every possible moiety does not constitute a written description of every species in a genus because it would not “reasonably lead” those skilled in the art to any particular species.
Amgen, Inc. v. Chugai Pharmaceutical Co., Ltd., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) states that “it is well established in our law that conception of a chemical compound requires that the inventor be able to define it so as to distinguish it from other materials, and to describe how to obtain it”.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or structural features common to the members of the genus, which features constitute a substantial portion of the genus, so that one of skill in the art can “visualize or recognize” the members of the genus (Emphasis added). Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997).
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. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; 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).
In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B(i), the court states, "An adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention."
Courts have stated that “[i]n claims involving [non-genetic] chemical materials, generic formulae usually indicate with specificity what the generic claims encompass. One skilled in the art can distinguish such a formula from others and can identify many of the species that the claims encompass. Accordingly, such a formula is normally an adequate description of the claimed genus.” Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089 (1998). (emphasis added).
There is no such specificity here, nor could one skilled in the art identify any particular compound encompassed by the claims. Specifically, Applicant fails to disclose any other conjugates and glycosylated chlorin derivatives, besides those identified in the specification, and in relation to the above, these disclosed species or subgenre do not represent the substantial variety covered by the genus of conjugates and glycosylated chlorin derivatives.
With regard to the functional definition of targeting substance and a cytotoxin, the specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116) because the specification contains almost no information by which a person of ordinary skill in the art would understand that the inventors possessed the all of the recited conjugates. At best, it simply indicates that one should test an inordinate number of moieties to see if the compounds can perform the required functions. In this connection, the specification contains no generic structural characteristics of a targeting substance or cytotoxins, besides those compounds instantly disclosed, see In re ’318 Patent Infringement Litigation, 583 F.3d 1317, 1327 (Fed. Cir. 2009) (“[A]t the end of the day, the specification, even read in light of the knowledge of those skilled in the art, does no more than state a hypothesis and propose testing to determine the accuracy of that hypothesis. That is not sufficient.”).
The Examiner acknowledges that a working example or exemplified embodiment is not necessarily a requirement for description. However, where a generic claim term is present in a claim, as in the present application, and defined only by functional characteristics, the specification must convey enough information, e.g., via sufficient representative examples, to indicate invention of species sufficient to constitute the genus. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 967 2 (Fed. Cir. 2002). The written description requirement “requires a description of an invention, not an indication of a result that one might achieve if one made that invention.” Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997); see also Novozymes A/S v. DuPont Nutrition Biosciences APS, 723 F.3d 1336, 1350 (Fed. Cir. 2013) (“A patent...‘is not a reward for the search, but compensation for its successful conclusion.’ ... For that reason, the written description requirement prohibits a patentee from ‘leaving it to the ... industry to complete an unfinished invention.’” (citations omitted)).
Accordingly, the specification lacks adequate written description for the recited conjugates of a targeting substance and a cytotoxin or glycosylated chlorin derivatives.
Claims 1 and 3-9 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 rejected claims cover conjugates comprising a cell binding ligand which embraces ligands that are not antibodies, or antigen-binding fragments thereof.
To satisfy the written-description requirement, the specification must describe every element of the claimed invention in sufficient detail so that one of ordinary skill in the art would recognize that the inventor possessed the claimed invention at the time of filing. Vas-Cath, 935 F.3d at 1563; see also Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997) (patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention”); In re Gosteli, 872 F.2d 1008, 1012 (Fed. Cir. 1989) (“the description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed”).
With regard to the recited targeting moieties, the following applies:
Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 94 USPQ2d 1161 (Fed. Cir. 2010) states that “...a generic claim may define the boundaries of a vast genus of chemical compounds...the question may still remain whether the specification, including the original claim language, demonstrates that the applicant invented species sufficient to support a claim to a genus”. See page 1171.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
See also Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996) (a “laundry list” disclosure of every possible moiety does not constitute a written description of every species in a genus because it would not “reasonably lead” those skilled in the art to any particular species.
Amgen, Inc. v. Chugai Pharmaceutical Co., Ltd., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) states that “it is well established in our law that conception of a chemical compound requires that the inventor be able to define it so as to distinguish it from other materials, and to describe how to obtain it”.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or structural features common to the members of the genus, which features constitute a substantial portion of the genus, so that one of skill in the art can “visualize or recognize” the members of the genus (Emphasis added). Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997).
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. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; 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).
In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B(i), the court states, "An adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention."
Here, Applicant desires patent protection for medicaments comprising targeting moieties for the claimed antibody-drug conjugates (ADC’s). However, other than antibodies and their functional fragments, the specification does not provide adequate written description of the claimed genus of the targeting moieties within the context of the claimed ADC’s. This is because antibodies are well characterized, functionally and structurally, in the prior art. Specifically, antibodies are heavy (~150 kDa) globular plasma proteins. The size of an antibody molecule is about 10 nm. They have sugar chains (glycans) added to conserved amino acid residues. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM. The Ig monomer is a "Y"-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds. Each chain is composed of structural domains called immunoglobulin domains. These domains contain about 70–110 amino acids and are classified into different categories (for example, variable or IgV, and constant or IgC) according to their size and function. They have a characteristic immunoglobulin fold in which two beta sheets create a "sandwich" shape, held together by interactions between conserved cysteines and other charged amino acids.
Some parts of an antibody have the same functions. The arms of the Y, for example, contain the sites that can bind to antigens (in general, identical) and, therefore, recognize specific foreign objects. This region of the antibody is called the Fab (fragment, antigen-binding) region. It is composed of one constant and one variable domain from each heavy and light chain of the antibody. The paratope is shaped at the amino terminal end of the antibody monomer by the variable domains from the heavy and light chains. The variable domain is also referred to as the FV region and is the most important region for binding to antigens. To be specific, variable loops of β-strands, three each on the light (VL) and heavy (VH) chains are responsible for binding to the antigen. These loops are referred to as the complementarity determining regions (CDRs). 1 There are three CDRs (CDR1, CDR2 and CDR3), arranged non-consecutively, on the amino acid sequence of a variable domain of an antigen receptor. Since the antigen receptors are typically composed of two variable domains (on two different polypeptide chains, heavy and light chain), there are six CDRs for each antigen receptor that can collectively come into contact with the antigen. A single antibody molecule has two antigen receptors and therefore contains twelve CDRs total. There are three CDR loops per variable domain in antibodies.2
However, in contrast to the function of antibodies and their functional fragments, as outlined above, the other targeting moieties covered by the claims are not sufficiently characterized by the specification or state of the art in such a manner that those of ordinary skill would understand that the instant inventors knew how to they would be structurally integrated into the instant ADC’s. In particular, the specification does not provide any examples of the other targeting moieties which function within the context of the claimed ADC’s, and in this way, the specification does not present the requisite examples of ligands and targeting moieties, other than antibodies, given the breadth and variety of these groups covered by the claims. Specifically, the specification does not disclose a sufficient description of a representative number of species, either by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, of those moieties which can be used in the claimed ADC’s.
Moreover, the specification contains almost no information by which a person of ordinary skill in the art would understand that the inventors possessed these moieties, which have the structural characteristics, as outlined above, which can properly function in the claimed ADC’s. In this connection, the specification contains no structural or specific functional characteristics of the recited proteins and polypeptides. At best, it simply indicates that one should test an infinite number of compounds and moieties to see if they function in the claimed ADC’s, which is indicative of a lack of written description, see In re ’318 Patent Infringement Litigation, 583 F.3d 1317, 1327 (Fed. Cir. 2009) (“[A]t the end of the day, the specification, even read in light of the knowledge of those skilled in the art, does no more than state a hypothesis and propose testing to determine the accuracy of that hypothesis. That is not sufficient.”).
Accordingly, the specification lacks adequate written description for the recited targeting moieties.
Claims 1-9 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The rejected claims cover conjugates comprising substances that bind a target substance on the surface of tumor cells. Claim 4 recites specific targets.
Here, a genus of substances that can bind to a substance on a tumor cell lacks written description because the recited functional definition of a substance that binds a substance on a tumor cells does not describe the invention.
Here, the genus of substances, e.g., peptides, cannot be adequately described by functional characteristics of preferential binding, even where there is disclosed or known correlations between structure and function.
The Examiner recognizes that the disclosed targets may be fully characterized. Previously, disclosing a bonding target satisfied the written description requirement for a claim to an antibody or protein that binds the target. The Federal Circuit's decisions in Enzo Biochem v. Gen-Probe, Inc., 323 F.3d 956, 964 (Fed. Cir. 2002) and Noelle v. Lederman, 355 F. 3d 1341 (Fed. Cir. 2004) which purportedly set forth what has been called the "newly characterized antigen" test. Also, the PTO's Written Description Training Materials Revision dated March 25, 2008, provide an example (Example 13) embodying the test set forth in Enzo and Noelle.
However, reliance on Enzo and Noelle is misplaced. While the court in Noelle did discuss what is referred to as the "newly characterized antigen" test, the Federal Circuit has recently rejected such a test. Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378-79 (Fed. Cir. 2017). At issue in Amgen was the district court's jury instruction which read:
In the case of a claim to antibodies, the correlation between structure and function may also be satisfied by the disclosure of a newly characterized antigen by its structure, formula, chemical name, or physical properties if you find that the level of skill and knowledge in the art of antibodies at the time of filing was such that the production of antibodies against such an antigen was conventional and routine.
Id. at 1376. The Federal Circuit concluded that the instruction was "not legally sound and [was] not based on any binding precedent." Id. In reaching its conclusion the Federal Circuit reviewed the cases which purported to set forth the newly characterized antigen test including Noelle. Id. at 1376-77. The court concluded that in each of the prior cases the reference to the newly characterized antigen test was dicta and not binding precedent. Id.
The Federal Circuit went on to find that the newly characterized antigen test ran afoul of the Federal Circuit's precedent in Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en bane). Id. at 1378. The court noted that the focus of the inquiry is whether the written description contains enough information about the claimed products. Id. The court held that describing the antigens, which was not the claimed invention, did not satisfy the written description requirement when (“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... does not tell you anything at all about the structure of the antibody [emphasis applied]"); 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 a memo issued in February 2018, USPTO, Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, Feb. 22, 2018 (available at https://www.usnto.gov/sites/defauH/files/documents/amgen 22feb2018.pdf) the PTO issued a clarification regarding the law of written description as it applies to antibodies stating:
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.
The Memo goes on to state that
"Examples in the 2008 Written Description Training Materials Are Outdated." and should NOT be relied upon as reflecting the current state of the law. Id. at 2. The Memo explains that
USPTO personnel should continue to follow the guidance in the MPEP regarding written description (see, e.g., MPEP 2161.01 and 2163 ), except insofar as MPEP 2163 indicates that disclosure of a fully characterized antigen may provide written descriptive support of an antibody to that antigen.
Id.
The instant claims present the same deficiency as the claims in Amgen where there is no evidence that knowledge of the chemical structure of a target gives the required kind of structure-identifying information about the corresponding peptides that it binds. As in Amgen, the instant claims attempt to describe tumor binding moieties by describing the target to which the peptides bind. Moreover, there is nothing else in the disclosure that describes the peptides as required by the test set forth in Ariad.
Moreover, regard to the functional definition the binding moieties, the specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116) because the specification contains almost no information by which a person of ordinary skill in the art would understand that the inventors possessed the all of the recited compounds. At best, it simply indicates that one should test an inordinate number of moieties to see if the compounds can perform the required binding. In this connection, the specification contains no generic structural characteristics of those substances that bind tumor cells, see Patent Infringement Litigation, 583 F.3d 1317, 1327 (Fed. Cir. 2009) (“[A]t the end of the day, the specification, even read in light of the knowledge of those skilled in the art, does no more than state a hypothesis and propose testing to determine the accuracy of that hypothesis. That is not sufficient.”).
Accordingly, the specification lacks adequate written description for the recited conjugates comprising substances that bind a target substance on the surface of tumor cells.
Claims 1-9 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.
The intended structure of the glycosylated chlorin derivative is not defined. The description in the specification bridging pages 8 and 9 provides only examples and those of ordinary skill would not know the structures of the recited compounds.
Claim 2 recites a broad range limitation of peptide or ligand together with a narrow limitation of antibody that falls within the broad limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is merely exemplary of the remainder of the claim.
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.
Claims 6-9 are 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.
Claims 6-9 do not structurally or functionally limit the elements of the recited medicament of claim 1.
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.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over
Olsen et al., Biochemical Pharmacology, Volume 144, 2017, Pages 63-77 (Olsen) or Yip et al., Mol. Pharmaceutics 2 April 2007; 4 (2): 241–251 (Yip); in view of:
WO 2018/101434 (WO 434) as evidenced by Machine Translation of WO 2018/101434 downloaded 23 Sept. 2026 from:
https://patents.google.com/patent/JPWO2018101434A1/en?oq=WO+2018101434 (Machine translation of WO 2018/101434); and
Soyama et al., Translational Oncology 14 (2021) 101005 (Soyama).
The primary references teach immunotoxin conjugates for killing EGFR-expressing tumor cells by photoirradiation with EGF-saporin or cetuximab-saporin conjugates together with a photosensitizing agent.
Olsen relates to possible mechanisms and approaches for overcoming photodynamic therapy (PDT)-resistance (title), and teaches that resistance to PDT in the human breast cancer cell line MA11 was induced after repeated PDT using disulfonated meso-tetraphenyl clorin (TPCS2a) as a photosensitizer; that the TPCS2a-PDT-resistant cells had acquired higher proliferative capability and enhanced EGFR expression; that photochemical internalization (PCI) of EGF-saporin induced potent cytotoxicity in both MA11 and MA1 1/TR cells; and that this research suggests PCI as a rational therapeutic intervention to eliminated PDT-resistant cells (abstract). More specifically, Olsen states that in the PCI protocol, the cells were first cultured in the copresence of TPCS2a and EGF-saporin, and then exposed to light following the PDT protocol (section 2.3); and that as a result, the targeting of epithelial growth factor receptors (EGFRs) with TPCS2a-based PCI of EGF-saporin elicited a potent cytotoxic response when compared to treatment with only PDT or EGF-saporin (section 3.8; figure 9).
Yip teaches that cetuximab-saporin cytotoxicity was enhanced by photochemical internalization (PCI) in EGFR-positive cancer cells (title); that cetuximab-saporin is an immunotoxin that targets EGFR-expressing cells; that a photochemical treatment synergistically enhanced the cytotoxicity of the immunotoxin cetuximab-saporin in three different EGFR-expressing cancer cell lines derived from different tumor tissues (such as A-431 cells); and that in conclusion, PCI enhances the cytotoxic selectivity of the cetuximab-saporin immunotoxin in EGFR-expressing cells (abstract; figures 3 and 4).
Moreover, Yip teaches that meso-tetraphenyl porphyrin disulphonate (TPPS2a) was used as a photosensitizer (PS) in said photochemical treatment (section entitled "Drugs and Chemicals"); and that said PCI was either a "light after" PCI wherein cells were first co-incubated with TPPS2a and cetuximab-saporin and then exposed to light, or a "light-first" PCI wherein cells were incubated with the immunotoxin immediately after light exposure (section entitled "Photochemical Treatments").
Olsen and Yip do not explicitly teach the use of a glycosylated chlorin derivative as the photosensitizing agent. However, the use of the instant glycosylated chlorin derivatives as photosensitizing agents was well within the puriview of those of ordinary skill. It is for that proposition the rejection joins WO 434.
Specifically, WO 434 describes the derivatives of glycosylated chlorin e6 represented by general formula 1:
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WO 434 teaches that said glycosylated chlorin e6 derivatives are safer for living organisms than a conventional chlorin compound (sodium talaporphine) and have superior tumor-killing effects on cells via photodynamic therapy (specifically, photoirradiation at a wavelength of 660 nm) (paragraph 11; tables 3-6), see also Machine translation of WO 2018/101434 at [Evaluation method of phototoxicity].
Moreover Soyama teaches photodynamic therapy using mannose-conjugated chlorin e6 (M-chlorin e6), targets mannose receptors highly expressed on M2-TAMs. M-chlorin e6 accumulated more in tumor tissue than normal skin tissue of syngeneic model mice and was more rapidly excreted than the second-generation photosensitizer talaporfin sodium. Furthermore, M-chlorin e6 PDT significantly reduced the volume and weight of tumor tissue. Flow cytometric analysis revealed that M-chlorin e6 PDT decreased the proportion of M2-TAMs and increased that of anti-tumor macrophages, M1-like TAMs. M-chlorin e6 PDT also directly damaged and killed cancer cells in vitro. Our data indicate that M-chlorin e6 is a promising new therapeutic agent for cancer PDT.
In this regard, a person skilled in the art could use the glycosylated chlorin e6 derivative described in the secondary references as the photosensitizing agent to enhance the effectiveness of tumor inhibition resulting from photoirradiation and safety. In particular, those of ordinary skill could have applied the recited glycosylated chlorin derivatives in the manner claimed and in a predictable fashion for the purposes of obtaining the recited medicaments for treating cancer. As outlined above, the primary references teach immunotoxin conjugates for killing EGFR-expressing tumor cells by photoirradiation with EGF-saporin or cetuximab-saporin conjugates together with a photosensitizing agent. The secondary references are added for the proposition glycosylated chlorin derivatives are applicable to these combinations of immunotoxins and photosensitizing agents during photodynamic therapy. Specifically, the references teach that the particular known technique of using glycosylated chlorin derivatives as a photosensitizing agent in photodynamic therapywas recognized as part of the ordinary capabilities of one skilled in the art. In this manner, those of ordinary skill would have recognized that applying the known technique to those medicaments that use photosensitizing agents, such as those taught by the primary references, would have yielded predictable results. Accordingly, using the instant glycosylated chlorin derivative as the photosensitizing agents for immunotoxin photodynamic therapy would have been prima facie obvious.
Claims 6-9 recite method steps that do not modify the recited medicaments. Nonetheless, the applied references substantially teach the recited medicaments and their use in photodynamic therapy. Any observed pharmacological effects would have been a necessary aspect of those medicaments disclosed by the applied references, see MPEP 2112.01 (“Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id”).
Conclusion
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/KARL J PUTTLITZ/ Primary Examiner, Art Unit 1646
1 See https://en.wikipedia.org/wiki/Antibody
2 See https://en.wikipedia.org/wiki/Complementarity-determining_region
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