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 .
Claims 2, 8, 17, 20-30 have been canceled. Claims 31-34 have been added. Claims 1, 3-7, 9-16, 18, 19, 31-34 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.
Written Description
Claims 1, 3-7, 9-16, 18, 19, 31-34 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 genetically modified bovine whose genome comprises an inactivated prolactin receptor (PRLR) gene encoding a PRLR protein comprising histidine to arginine substitution at position 188, wherein the bovine is capable of producing milk without being pregnant when the bovine is female, does not reasonably provide enablement for claims 1, 12, 14 as broadly written, making any non-human mammal or progeny as broadly encompassed by claims 1, 12, 14 other than a bovine whose genome comprises an inactivated PRLR gene, making any modification to the histidine at position 188 as required in claim 3, 13, 15 other than histidine to arginine. 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/use the invention commensurate in scope with these claims.
Claim 1 is drawn to a non-human mammal or progeny thereof comprising an edited chromosomal sequence that alters expression or activity of a prolactin receptor (PRLR) protein, wherein the non-human mammal produces milk without having been pregnant and wherein the edited chromosomal sequence encodes a modification of one or more amino acids corresponding to positions 105 to 205 of the PRLR protein of SEQ ID NO: 3 or 4.
The specification lacks written description for making any genetically modified non-human mammal as broadly encompassed by claims 1, 12, 14 other than a genetically modified bovine. The scope of non-human mammal encompasses any rat, beaver, squirrel, groundhog, muskrat, hamster, capybara, chinchilla, porcupine, gerbil, dog, cat, pig, sheep, horse, cow, deer, rabbit, elephant, giraffe, skunk, whale, dolphin, gazelle, antelope, elk, tiger, leopard, cheetah, dingo, wolf, mole, vole, otter, platypus,…etc. The specification is limited to making a genetically modified bovines (Example 1). The specification does not correlate the transgenic rat, beaver, squirrel, groundhog, muskrat, hamster, capybara, chinchilla, porcupine, gerbil, dog, cat, pig, sheep, horse, deer, rabbit, elephant, giraffe, skunk, whale, dolphin, gazelle, antelope, elk, tiger, leopard, cheetah, dingo, wolf, mole, vole, otter, platypus,…etc. Accordingly, the concept lacks written description except for transgenic bovines.
The specification lacks written description for making any genetically modified non-human mammal having any structure that is capable of producing milk without being pregnant when the bovine is female as broadly encompassed by claims 1, 12, 14.
The claims encompass any “modification of one or more amino acids” from 105-205 of the PRLR protein of SEQ ID NO: 3 or 4 that allows the mammal to produce milk without having been pregnant. Claims 1, 12, 14 encompass genetically modified males or females who have not been pregnant.
Viitala (FI 120911) taught genetic markers in milk production and polymorphisms of the PRLR including T557C (see detailed description of translation, specifically pg 4). Viitala did not teach the T557C substitution caused lactation in a non-human mammal without having been pregnant.
McGrath (20020058621) taught “cows will not produce milk unless they have a calf” (para 5) and provides a means of inducing lactation in cows “that have never been pregnant” (para 3), “which are no longer capable of becoming pregnant” (para 30), or “non-pregnant” (claim 16, 18, 19) (para 45) using hormones (claim 1).
Stonstegard (20190223417) taught a non-human mammal whose genome comprises a truncated PRLR allele that exhibit less milk reduction in the summer (i.e. increased milk production in the summer) (para 8-9). Stonstegard did not teach the cows were pregnant or previously pregnant as required in claim 1. The PRLR is about 581 amino acids (para 14, Fig. 1). Stonstegard using CRISPR (para 10) and nuclear transfer (para 11) using an insertion, deletion, or mutation of the reading frame (10). Stonstegard taught the truncation is missing up to at least 148 amino acids but did not teach modifying amino acids 105-205 or doing so in the amino acid sequence of SEQ ID NO: 3 or 4 as required in claim 1. Stonstegard did not teach the bovines produced milk without having been pregnant as required in claim 1.
Amino acids 105-205 of PRLR were described by Stonstegard as well as Scott in 1992, and the amino acid sequence of SEQ ID NO: 4 was described by Scott (Mol. & Cell. Endocrin., 1992, Vol. 89, pg 47-58).
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Example 1 is limited to designing gRNA and a repair template to histidine to make an arginine substitution at position 188 of the PRLR protein of SEQ ID NO: 3 or 4 (pg 51-53). Example 2 (pg 53) is prophetic and suggests injecting Cas9, gRNA and the repair template into 1-cell bovine zygotes. Example 3 (pg 53) is prophetic and suggests screening the cows for the proper histidine to make an arginine substitution at position 188. Example 4 (pg 54) describes prolactin receptor sequences with the H118R substitution and transcript variants. Example 5 (pg 56) compares editing frequencies using two types of Cas9.
The specification does not exemplify obtaining any genetically modified non-human mammal whose genome has a modified prolactin gene as required in claims 1, 12, 14. The specification does not teach any genetically modified non-human mammal with a modified prolactin gene that produces milk without having been pregnant as required in claims 1, 12, 14. The specification does not teach making any non-human male mammal that produces milk as broadly encompassed by claims 1, 12, 14. The specification does not correlate female non-human mammals to male non-human mammals as broadly encompassed by claims 1, 12, 14. The specification does not correlate the H188R substitution to any “modification of one or more amino acids” from 105-205 of the PRLR protein of SEQ ID NO: 3 or 4 as broadly encompassed by claims 1, 12, 14. The specification does not provide adequate guidance that an H188R substitution or any “modification of one or more amino acids” from 105-205 of the PRLR protein of SEQ ID NO: 3 or 4 allows the mammal to produce milk without being pregnant. The specification does not correlate the H188R substitution to any “modification corresponding” to any “histidine residue at position 188” of the PRLR protein of SEQ ID NO: 3 or 4 as broadly encompassed by claims 3, 13, 15. The specification does not correlate the H188R substitution to any “histidine to arginine substitution corresponding to the histidine residue at position 188” of the PRLR protein of SEQ ID NO: 3 or 4 as broadly encompassed by claims 3, 13, 15 other than ---a histidine to arginine substitution at position 188---. The specification does not correlate the H188R or any other “modification” at positions 105-205 to “reduced or no functional PRLR protein activity as required in claim 5.
Accordingly, the concept lacks written description.
Enablement
Claims 1, 3-7, 9-16, 18, 19, 31-34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The specification does not enable making any genetically modified non-human mammal as broadly encompassed by claims 1, 12, 14 other than a genetically modified bovine. The scope of non-human mammal encompasses any rat, beaver, squirrel, groundhog, muskrat, hamster, capybara, chinchilla, porcupine, gerbil, dog, cat, pig, sheep, horse, cow, deer, rabbit, elephant, giraffe, skunk, whale, dolphin, gazelle, antelope, elk, tiger, leopard, cheetah, dingo, wolf, mole, vole, otter, platypus,…etc. The specification is limited to making a genetically modified bovines (Example 1). The specification does not correlate the transgenic rat, beaver, squirrel, groundhog, muskrat, hamster, capybara, chinchilla, porcupine, gerbil, dog, cat, pig, sheep, horse, deer, rabbit, elephant, giraffe, skunk, whale, dolphin, gazelle, antelope, elk, tiger, leopard, cheetah, dingo, wolf, mole, vole, otter, platypus,…etc.
The specification does not enable making any genetically modified non-human mammal having any structure that is capable of producing milk without being pregnant when the bovine is female as broadly encompassed by claims 1, 12, 14.
The claims encompass any “modification of one or more amino acids” from 105-205 of the PRLR protein of SEQ ID NO: 3 or 4 that allows the mammal to produce milk without having been pregnant. Claims 1, 12, 14 encompass genetically modified males or females who have not been pregnant.
McGrath (20020058621), Viitala (FI 120911), Stonstegard (20190223417) and Scott (Mol. & Cell. Endocrin., 1992, Vol. 89, pg 47-58) are described above.
The Examples are described above.
The specification does not exemplify obtaining any genetically modified non-human mammal whose genome has a modified prolactin gene as required in claims 1, 12, 14. The specification does not teach any genetically modified non-human mammal with a modified prolactin gene that produces milk without having been pregnant as required in claims 1, 12, 14. The specification does not teach making any non-human male mammal that produces milk as broadly encompassed by claims 1, 12, 14. The specification does not correlate female non-human mammals to male non-human mammals as broadly encompassed by claims 1, 12, 14. The specification does not correlate the H188R substitution to any “modification of one or more amino acids” from 105-205 of the PRLR protein of SEQ ID NO: 3 or 4 as broadly encompassed by claims 1, 12, 14. The specification does not provide adequate guidance that an H188R substitution or any “modification of one or more amino acids” from 105-205 of the PRLR protein of SEQ ID NO: 3 or 4 allows the mammal to produce milk without being pregnant. The specification does not correlate the H188R substitution to any “modification corresponding” to any “histidine residue at position 188” of the PRLR protein of SEQ ID NO: 3 or 4 as broadly encompassed by claims 3, 13, 15. The specification does not correlate the H188R substitution to any “histidine to arginine substitution corresponding to the histidine residue at position 188” of the PRLR protein of SEQ ID NO: 3 or 4 as broadly encompassed by claims 3, 13, 15 other than ---a histidine to arginine substitution at position 188---. The specification does not correlate the H188R or any other “modification” at positions 105-205 to “reduced or no functional PRLR protein activity as required in claim 5.
The specification fails to overcome the unpredictability of inducing lactation in any non-human female mammal without having been pregnant as described by McGrath (20020058621).
The specification fails to overcome the unpredictability of inducing lactation in any non-human female mammal with a T557C substitution without having been pregnant as described by Viitala (FI 120911).
Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make/use the non-human mammal of claim 1, the non-human mammalian cell of claim 12, or perform the method of claim 14.
The art at the time of filing did not reasonably teach or suggest making/using a non-human mammal, progeny thereof, or non-human mammalian cell comprising an edited chromosomal sequence that alters expression or activity of a prolactin receptor (PRLR) protein, wherein the non-human mammal produces milk without having been pregnant and wherein the edited chromosomal sequence encodes a modification of one or more amino acids corresponding to positions 105 to 205 of the PRLR protein of SEQ ID NO: 3 or 4 as required in claims 1 and 12 or performing the method of making them in claim 14.
Conclusion
No claim is allowed.
Inquiry concerning this communication or earlier communications from the examiner should be directed to Michael C. Wilson who can normally be reached at the office on Monday through Friday from 9:30 am to 6:00 pm at 571-272-0738.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638