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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`BIOFRONTERA INCORPORATED,
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`BIOFRONTERA BIOSCIENCE GMBH,
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`BIOFRONTERA PHARMA GMBH,
`
`AND
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`BIOFRONTERA AG
`
`Petitioners
`
`v.
`
`DUSA PHARMACEUTICALS, INC.
`
`Patent Owner
`_____________________________
`
`PATENT 10,357,567
`
`_____________________________
`
`DECLARATION OF HOWARD ROGERS, MD, PHD
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`TABLE OF CONTENTS
`I. 
`Education and Experience ............................................................................... 1 
`Compensation .................................................................................................. 3 
`II. 
`III.  Legal Considerations ....................................................................................... 4 
`A.  Anticipation ........................................................................................... 4 
`B. 
`Obviousness ........................................................................................... 5 
`C. 
`Claim Construction ............................................................................... 8 
`IV.  Level of Ordinary Skill in the Art ................................................................... 9 
`V. 
`Task Summary ............................................................................................... 10 
`VI.  State of the Art ............................................................................................... 14 
`A. 
`5-Aminolevulinic Acid (ALA) Photodynamic Therapy ..................... 14 
`B. 
`Light Sources Utilized in ALA PDT ................................................... 18 
`C. 
`Treating Actinic Keratosis using PDT ................................................ 23 
`D.  Occlusion with plastic wrap to minimize transepidermal water loss
`and enhance penetration of ALA was well known ............................. 26 
`State of the Art Summary .................................................................... 30 
`E. 
`VII.  The ‘567 Patent .............................................................................................. 32 
`A. 
`The ‘567 Patent Description and Claims ............................................ 32 
`B. 
`‘567 Patent Application (U.S. Patent Application No. 15/869,164) ... 42 
`VIII.  Claim Construction ........................................................................................ 47 
`IX.  Application of the Prior Art to the Challenged Claims ................................. 48 
`A.  Ground 1: Claims 1-4 and 6-10 Are Taught by Willey ...................... 49 
`1. 
`Claim 1 ...................................................................................... 50 
`2. 
`Claim 1a .................................................................................... 51 
`3. 
`Claim 1b .................................................................................... 52 
`4. 
`Claim 1c .................................................................................... 54 
`5. 
`Claim 2 ...................................................................................... 57 
`6. 
`Claim 3 ...................................................................................... 58 
`7. 
`Claim 4 ...................................................................................... 61 
`8. 
`Claim 4a .................................................................................... 61 
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`C. 
`
`B. 
`
`9. 
`Claim 4b .................................................................................... 61 
`10.  Claim 4c .................................................................................... 62 
`11.  Claim 6 / Claim 7 ...................................................................... 62 
`12.  Claim 8 ...................................................................................... 64 
`13.  Claim 8a .................................................................................... 65 
`14.  Claim 8b .................................................................................... 66 
`15.  Claim 8c .................................................................................... 67 
`16.  Claim 8d .................................................................................... 70 
`17.  Claim 9 ...................................................................................... 70 
`18.  Claim 10 .................................................................................... 72 
`Ground 2 – Claim 3 Is Met by the Combination of Willey with
`Ameluz ................................................................................................ 73 
`1. 
`Claim 3 ...................................................................................... 74 
`Ground 3 – Claim 5 Is Met by the Combination of Willey with
`Sotiriou ................................................................................................ 79 
`2. 
`Claim 5 ...................................................................................... 81 
`D.  Ground 4: Claims 1-9 Are Taught by Noven Pharma ........................ 84 
`1. 
`Claim 1 ...................................................................................... 85 
`2. 
`Claim 1a .................................................................................... 87 
`3. 
`Claim 1b .................................................................................... 88 
`4. 
`Claim 1c .................................................................................... 90 
`5. 
`Claim 2 ...................................................................................... 92 
`6. 
`Claim 3 ...................................................................................... 95 
`7. 
`Claim 4 ...................................................................................... 99 
`8. 
`Claim 4a .................................................................................... 99 
`9. 
`Claim 4b .................................................................................. 100 
`10.  Claim 4c .................................................................................. 100 
`11.  Claim 5 .................................................................................... 101 
`12.  Claim 6 / Claim 7 .................................................................... 103 
`13.  Claim 8 .................................................................................... 105 
`14.  Claim 8a .................................................................................. 106 
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`X. 
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`15.  Claim 8b .................................................................................. 108 
`16.  Claim 8c .................................................................................. 109 
`17.  Claim 8d .................................................................................. 110 
`18.  Claim 9 .................................................................................... 110 
`Ground 5 – Claim 3 Is Met by the Combination of Noven Pharma and
`Fauteck .............................................................................................. 112 
`3. 
`Claim 3 .................................................................................... 114 
`Ground 6 – Claim 10 Is Met by the Combination of Noven Pharma
`with the BLU-U Operating Manual .................................................. 117 
`2. 
`Claim 10 .................................................................................. 119 
`Claim Charts ................................................................................................ 122 
`A.  Ground 1: Claims 1-4 and 6-10 are taught by Willey ....................... 122 
`B. 
`Ground 2: Claim 3 is met by the combination of Willey with
`Ameluz .............................................................................................. 131 
`Ground 3: Claim 5 is met by the combination of Willey with
`Sotiriou .............................................................................................. 134 
`D.  Ground 4: Claims 1-9 are taught by Noven Pharma ......................... 135 
`E. 
`Ground 5: Claim 3 is met by the combination of Noven Pharma with
`Fauteck. ............................................................................................. 149 
`Ground 6: Claim 10 is met by the combination of Noven Pharma with
`the BLU-U operating manual ............................................................ 152 
`XI.  Additional Remarks ..................................................................................... 152 
`
`E. 
`
`F. 
`
`C. 
`
`F. 
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`DECLARATION OF DR. HOWARD ROGERS
`I, Howard Rogers, declare as follows:
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`1.
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`2. My name is Howard Rogers. I am over the age of twenty-one (21) years,
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`of sound mind, and capable of making the statements set forth in this Declaration. I
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`am competent to testify about the matters set forth herein. All the facts and
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`statements contained herein are within my personal knowledge and they are, in all
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`things, true and correct.
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`3.
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`I have been asked by Biofrontera Incorporated, Biofrontera Bioscience
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`GmbH, Biofrontera Pharma GmbH, and Biofrontera AG
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`(collectively,
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`“Biofrontera”) to submit this declaration in support of their challenge to the validity
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`of all claims of U.S. Patent No. 10,357,567 (“the ‘567 patent”).
`
`I.
`
`Education and Experience
`4. My curriculum vita is attached as Exhibit 1004.
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`5.
`
`I am a board-certified dermatologist and a fellowship-trained Mohs
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`micrographic surgeon. I received a Bachelor of Science degree in Biology from
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`Harvard University in 1989, where I graduated magna cum laude. My undergraduate
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`thesis research focused on the immunological response of mast cells. I attended
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`medical school at Washington University School of Medicine in St. Louis from
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`1989-1996. I graduated with honors, with both an M.D. and a Ph.D. My Ph.D. thesis
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`involved seminal research into mechanisms of infectious immunity. At graduation,
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`I was awarded the Olin Fellowship (in recognition of my advanced medical research)
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`and the Yalem Dermatology Award (for excellence in Dermatology scholarship).
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`6.
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`I completed my internship in internal medicine at University Hospital
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`in Baltimore, Maryland. I completed my residency in dermatology at Washington
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`University School of Medicine in 2000 as the chief dermatological resident at Barnes
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`Hospital in St. Louis, MO. While a dermatology resident, I won numerous awards
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`including being elected chief resident.
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`7.
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`I practiced general and dermatologic surgery at the Chelsea Clinic in
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`Norwich, CT from 2000-2004. I then founded Advanced Dermatology, a private
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`dermatology practice specializing in skin cancer diagnosis, treatment and
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`prevention, in Norwich, CT. I completed a fellowship in Mohs micrographic surgery
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`and cutaneous surgical oncology specializing in difficult to treat skin cancers at the
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`Skin Cancer Center at the University of Cincinnati Hospital in Cincinnati, OH in
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`2008. Following this training, I founded a second dermatology office, Shoreline
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`Mohs Surgery, in Guilford, CT.
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`8.
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`I have nearly twenty-five years of experience with skin cancer
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`treatment and photodynamic therapy. My education and experience in photodynamic
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`therapy started with residency training in the procedure in 1997. Since then, in my
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`own private practice, I have treated patients with photodynamic therapy for a variety
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`of conditions for around 15 years. I have also served as an advisor to the American
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`Medical Association Relative Value Update Committee in defining photodynamic
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`therapy methods and work for incorporation into Current Procedural Terminology
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`and for procedure valuation in the Medicare physician fee schedule.
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`9.
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`I am an author or co-author on over twenty publications relating to
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`dermatology and skin cancer. I have also testified before Congress in 2019 on the
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`administrative, economic, and medical effects of prior authorization and step therapy
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`policies on practitioners and patients. I am board certified by the American Board of
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`Dermatology, and my fellowship training was accredited by the American College
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`of Mohs Micrographic Surgery. I have served on numerous committees and boards
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`of national dermatological organizations. My leadership in the field has been
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`recently recognized by election to the Presidency of the American College of Mohs
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`Surgery where I currently serve as Vice President and President-elect.
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`10. Having the foregoing knowledge and experience, I am well qualified to
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`offer the opinions I express in this declaration. A summary of my experience,
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`education, publications and other qualifications is provided in my CV, a copy of
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`which is submitted separately as Exhibit 1004.
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`II. Compensation
`11.
`In consideration for my services, my work on this case is being billed
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`to Biofrontera at an hourly rate of $600 per hour, independent of the outcome of this
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`proceeding. For any work requiring me to be away from the office, I am being
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`reimbursed at a daily rate of $8000/day. I am also being reimbursed for reasonable
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`expenses I incur in relation to my services provided for this proceeding.
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`III. Legal Considerations
`12.
`I understand from counsel that the following standards govern the
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`determination of whether a patent claim is invalid as anticipated by and/or obvious
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`in light of the prior art. I have applied these standards in my analysis of whether
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`claims of the ‘567 patent were anticipated and rendered obvious by January 12, 2018.
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`A. Anticipation
`13.
`I understand that patents or printed publications that qualify as prior art
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`can be used to invalidate a patent claim as anticipated or as obvious.
`
`14.
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`I understand that a patent claim is “anticipated” by a single prior art
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`reference if that reference discloses each element of the claim.
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`15.
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`I understand that the test for anticipation is performed in two steps.
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`First, the claims are interpreted to determine their meaning. Second, a potentially
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`invalidating prior art reference is analyzed on an element-by-element basis to
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`determine whether each claim element, as interpreted during the first step, is present
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`in that reference. If all of the elements of a patent claim are present in the prior art
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`reference, then that claim is anticipated and is therefore invalid.
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`16.
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`I further understand that a prior art reference can anticipate a patent
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`claim without expressly disclosing a feature or element of the claim if the missing
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`feature or element is necessarily present, or inherent, in the anticipating reference.
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`17.
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`I also understand that it is acceptable to examine extrinsic evidence
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`outside the prior art reference in determining whether a feature, while not expressly
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`discussed in the reference, is necessarily present within that reference.
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`B. Obviousness
`18.
`I understand that a claimed invention is not patentable for obviousness
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`if the differences between the invention and the prior art are such that the subject
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`matter as a whole would have been obvious at the time the invention was made to a
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`person having ordinary skill in the art to which the subject matter of the invention
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`pertains.
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`19.
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`I understand that a person of ordinary skill in the art is a hypothetical
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`person who is presumed to have known the relevant art at the time of the invention.
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`As discussed above, I understand that the relevant art for the purpose of this
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`declaration at least includes references that were published or publically available
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`before January 12, 2018, the filing date for the ‘567 patent.
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`20.
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`I have been instructed that a determination of obviousness requires
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`inquiries into: (1) the scope and content of the state of the art when the invention
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`was made; (2) the differences between the art and the claims of the patent at issue;
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`(3) the level of ordinary skill in the pertinent art when the invention was made; and,
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`(4) to the extent they exist, any secondary considerations, such as, unexpected
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`results, long-felt but unresolved needs, failure of others, etc.
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`21.
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`I understand that a claim can be found to be obvious if all the claimed
`
`elements were known in the prior art and one skilled in the art could have combined
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`the elements as claimed by known methods with no change in their respective
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`functions, and the combination would have yielded nothing more than predictable
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`and expected results to one of ordinary skill in the art.
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`22.
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`I understand that improper hindsight must not be used when comparing
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`the prior art to the invention for obviousness. Thus, a conclusion of obviousness
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`must be firmly based on the knowledge and skill of a person of ordinary skill in the
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`art at the time the invention was made.
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`23.
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`I have been informed that obviousness may also be shown by
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`demonstrating that it would have been obvious to modify what is taught in a single
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`piece of prior art to create the patented invention. I further understand that
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`obviousness may be demonstrated by showing that it would have been obvious to
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`combine the teachings of more than one item of prior art.
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`24.
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`I understand that in order for a combination of references or teachings
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`to render the claimed invention obvious, there must be some supporting rationale for
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`combining the cited references or teachings as proposed. I understand further that
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`prior art references themselves may provide a suggestion, motivation, or reason to
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`combine, but that at other times the linkage between two or more prior art references
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`is common sense.
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`25.
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`I have been informed that the application of the teaching, suggestion or
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`motivation test should not be rigidly applied, but rather is an expansive and flexible
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`test. For example, I have been informed that the common sense of a person of
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`ordinary skill in the art can serve as motivation for combining references.
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`26.
`
`In addition, I understand that a person of ordinary skill in the art must
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`have had a reasonable expectation of success in deriving the claimed invention from
`
`the combination of references or teachings. I understand that obviousness does not
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`require absolute predictability of success but instead requires only a reasonable
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`expectation of success.
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`27.
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`I further understand that exemplary rationales that may support a
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`conclusion of obviousness include: (1) simply arranging old elements in a way in
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`which each element performs the same function it was known to perform, and the
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`arrangement yields expected results; (2) merely substituting one element for another
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`known element in the field, and the substitution yields no more than a predictable
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`result; (3) the use of a known technique to improve similar methods or products in
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`the same way; (4) the application of a known technique to a known method or
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`product ready for improvement to yield predictable results; (5) combining elements
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`in a way that was “obvious to try” because of a design need or market pressure,
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`where there was a finite number of identified, predictable solutions; (6) whether
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`design incentives or other market forces in a field prompted variations in a work that
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`were predictable to a person of ordinary skill in the art; and (7) that some teaching,
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`suggestion, or motivation in the prior art would have led one of ordinary skill in the
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`art to modify the prior art reference or to combine prior art references to arrive at the
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`claimed invention, among other rationales.
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`C. Claim Construction
`28.
`I understand that terms appearing in the patent claims are to be
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`interpreted according to their “ordinary and customary meaning” at the time the
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`alleged invention was made in an inter partes review proceeding. I understand that
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`this date corresponds to the filing date of the ‘567 patent, which is January 12, 2018.
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`29.
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` In determining the ordinary and customary meaning, the words of a
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`claim are given their plain meaning as they would have been understood by a person
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`of ordinary skill in the art at the time of the alleged invention in light of the claims,
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`the specification, and the file history. I have followed this approach in my analysis,
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`and have applied the ordinary and customary meaning of those terms throughout my
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`analysis in this declaration.
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`IV. Level of Ordinary Skill in the Art
`30.
`I have been advised that for purposes of this declaration a person of
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`ordinary skill in the art is a hypothetical person who is presumed to know all of the
`
`relevant art as of January 12, 2018. I understand from counsel that (1) the educational
`
`level of the inventor; (2) the type of problems encountered in the art; (3) the prior art
`
`solutions to those problems; (4) the rapidity with which innovations are made; (5)
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`the sophistication of the technology; and (6) the educational level of active workers
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`in the field are non-exhaustive factors that provide a guide for determining the
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`appropriate level of ordinary skill in the art. I further understand that a person of
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`ordinary skill in the art is also a person of ordinary creativity. I have been instructed
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`by counsel that the relevant timeframe for assessing the validity of the claims of the
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`‘567 patent for the purposes of this declaration is assumed to be January 12, 2018.
`
`Unless otherwise specifically noted, all of my opinions expressed herein regarding
`
`a person of ordinary skill in the art apply to a person of ordinary skill in the art as of
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`January 12, 2018.
`
`31. By virtue of my education, experience, and training, I am familiar with
`
`the level of skill in the art of the ‘567 patent as of January 12, 2018. In my opinion,
`
`a person of ordinary skill in the art relevant to the ‘567 patent and its related
`
`applications would have had at least a Ph.D., M.D. or D.O., with background in
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`dermatology, cell biology, molecular biology, or a related field or at least 2-3 years
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`of professional experience in one or more of those fields.
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`V. Task Summary
`32.
`I have been asked to review the ‘567 patent. I have been asked to
`
`provide my opinion regarding the validity of the ‘567 patent from the perspective of
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`a person of ordinary skill in the art, having knowledge of the relevant art as of
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`January 12, 2018, the ‘567 patent’s filing date. The qualifications and abilities of
`
`such a person are described in Section IV above.
`
`33.
`
`In preparing this declaration, I have considered the available prior art,
`
`the ‘567 patent in its entirety, the prosecution history of the ‘567 patent, and the
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`general knowledge of those familiar with the field of dermatological photodynamic
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`therapy as of January 12, 2018. The references I discuss herein relate generally to
`
`dermatology and dermatological photodynamic therapy.
`
`34.
`
`I have also reviewed the following exhibits:
`
`Exhibit
`
`Description
`
`U.S. Patent No. 10,357,567 (“the ‘567 patent”).
`
`Excerpts from U.S. Patent Application No. 15/869,164 (“the ‘164
`Application”).
`
`Declaration of Dr. Howard Rogers MD, PHD (this document)
`
`CV of Dr. Howard Rogers MD, PHD
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`1001
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`1002
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`1003
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`1004
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`Exhibit
`
`Description
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`PCT Publication No. WO 96/06602 (“Noven Pharma”).
`
`Sakamoto FH, Torezan L, Anderson RR. Photodynamic therapy
`for acne vulgaris: a critical review from basics to clinical
`practice: part II. Understanding parameters for acne treatment
`with photodynamic therapy. J Am Acad Dermatol. 2010
`Aug;63(2):195-211 (“Sakamoto”).
`
`Berardesca E, Vignoli GP, Fideli D, Maibach H. Effect of
`occlusive dressings on the stratum corneum water holding
`capacity. The American Journal of the Medical Sciences. 1992
`Jul;304(1):25-28 (“Berardesca”).
`
`Fauteck JD, Ackermann G, Birkel M, Breuer M, Moor AC,
`Ebeling A, Ortland C. Fluorescence characteristics and
`pharmacokinetic properties of a novel self-adhesive 5-ALA
`patch for photodynamic therapy of actinic keratoses. Arch
`Dermatol Res. 2008 Feb;300(2):53-60 (“Fauteck”).
`
`U.S. Patent Publication No. US2009/0324727 A1
`(“Biofrontera”).
`
`Ameluz Prescribing Information (2016) (“Ameluz”).
`
`Levulan Label (2002).
`
`BLU-U Operating Manual (2006).
`
`Willey A, Anderson RR, Sakamoto FH. Temperature-modulated
`photodynamic therapy for the treatment of actinic keratosis on
`the extremities. Dermatologic Surgery. 2014 Oct;40(10):1094-
`1102. (“Willey”).
`
`Calderhead RG. Light-emitting diode phototherapy in
`dermatological practice in lasers in dermatology and medicine.
`Lasers in Dermatology and Medicine. 2011 Aug:231-265.
`(“Calderhead”).
`
`
`
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`Exhibit
`
`Description
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`Palm M., Goldman PM. Aminolevulinic acid: actinic keratosis
`and photorejuvenation. In: Gold M.H., editor. Photodynamic
`Therapy in Dermatology. Springer Science and Business Media,
`LLC. 2011 Nov:5-30. (“Palm”).
`
`MacCormack MA. Photodynamic therapy in dermatology: an
`update on applications and outcomes. Semin Cutan Med Surg.
`2008 Mar;27(1):52-62. (“MacCormack”).
`
`Sotiriou E, Apalla Z, Maliamani F, Zaparas N, Panagiotidou D,
`Ioannides D. Intraindividual, right-left comparison of topical 5-
`aminolevulinic acid photodynamic therapy vs. 5% imiquimod
`cream for actinic keratoses on the upper extremities. J Eur Acad
`Dermatol Venereol. 2009 Sep;23(9):1061-5. (“Sotiriou”).
`
`Bissonnette R. Photodynamic therapy. In: Gold M.H., editor.
`Photodynamic Therapy in Dermatology. Springer Science and
`Business Media, LLC; New York, NY, USA: 2011. pp. 221–229.
`(“Bissonnette”).
`
`McLaren G. Photodynamic therapy. In; Pfenninger and Fowler's
`procedures for primary care. Third Ed. Mosby Elsevier;
`Philadelphia, PA: 2011. pp 397-400. (“McLaren”).
`
`Harris DR. Percutaneous absorption and the surface area of
`occluded skin: a scanning electron microscopic study. British
`Journal of Dermatology. 1974; 91(27-32). (“Harris”).
`
`Levulan Label (2009).
`
`Wachowska et al., Aminolevulinic acid (ALA) as a prodrug in
`photodynamic therapy of cancer. Molecules. 2011 May;16(5):
`4140-4164. (“Wachowska”).
`
`Agostinis et al. Photodynamic therapy of cancer: an update. CA:
`A Cancer Journal for Clinicians. 2011 May;61(4):250-281.
`(“Agostinis”).
`
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`Exhibit
`
`Description
`
`Wolf P., Rieger E. and Kerl H. Topical photodynamic therapy
`with endogenous porphyrins after application of 5-
`aminolevulinic acid: an alternative treatment modality for solar
`keratoses, superficial squamous cell carcinomas, and basal cell
`carcinomas? Journal of the American Academy of Dermatology
`28.1 (1993): 17-21 (“Wolf”).
`
`Jeffes E., McCullough J., Weinstein G., Fergin P., Nelson J.,
`Shull T., Simpson K., Bukaty L., Hoffman W., Fong N.
`Photodynamic therapy of actinic keratosis with topical 5-
`aminolevulinic acid. A pilot dose-ranging study. Arch Dermatol.
`1997 Jun;133(6):727-32 (“Jeffes”).
`
`Hongcharu W., Taylor C., Chang, Y., Aghasi, D., Suthamjariya,
`K., Anderson, R. Topical ALA-photodynamic therapy for the
`treatment of acne vulgaris. J Invest Dermatol. 2000
`Aug;115(2):183-92 (“Hongcharu”).
`
`Ozog, D., Rkein, A., Fabi, S., Gold M., Goldman, M., Lowe, N.,
`Martin, G., Munavalli, G. Photodynamic therapy: A clinical
`consensus guide. Dermatol Surg. 2016 Jul;42(7):804-27
`(“Ozog”).
`
`Aktilite CL128 Operators Manual with Metvixia (2008)
`(“Metvixia”).
`
`DUSA Levulan Press Release (1999).
`
`European Medicines Agency CHMP Assessment Report
`(excerpts) (2011).
`
`Affidavit of Duncan Hall
`
`Willey Pubmed Website Database Listing
`
`Sotiriou Pubmed Website Database Listing
`
`Fauteck Europe PMC Website Database Listing
`- 13 -
`
`1024
`
`1025
`
`1026
`
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`
`
`
`4844-3570-5844
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`

`

`
`
`Exhibit
`
`Description
`
`1035
`
`Rick K, Sroka R, Stepp H, Kriegmair M, Huber RM, Jacob K,
`Baumgartner R. Pharmacokinetics of 5-aminolevulinic acid-
`induced protoporphyrin IX in skin and blood. J Photochem
`Photobiol B. 1997 Oct;40(3):313-9 (“Rick”).
`
`
`VI. State of the Art
`35. The ‘567 patent describes photodynamic therapy with topically applied
`
`ALA, using occlusion with low density polyethylene (“LDPE”) film, followed by
`
`the application of light. Ex. 1001 at Abstract, Claims 1-10. In the sections below, I
`
`briefly summarize what was known about treating actinic keratosis using topically
`
`applied ALA and photodynamic therapy, the use of occlusion to enhance penetration
`
`of topically applied drug substances such as ALA, and the use of different light
`
`sources for photodynamic therapy before the ‘567 patent’s filing date.
`
`A.
`36.
`
`5-Aminolevulinic Acid (ALA) Photodynamic Therapy
`In photodynamic therapy (“PDT”), a photosensitizing compound (or a
`
`photosensitizing compound precursor) is applied to an area of the skin surface to be
`
`treated and then exposed to activating light in order to destroy precancerous skin
`
`cells called lesions. Ex. 1015 [Palm] at 5. The photosensitizing molecule can be
`
`absorbed directly into the skin or when a photosensitizing precursor molecule is
`
`applied, the photosensitizer can be generated in situ within the absorbing cells. Ex.
`
`
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`1015 [Palm] at 5. Once absorption and/or generation of the photosensitizer has
`
`occurred, light is applied to the photosensitized skin cells. Ex. 1015 [Palm] at 5; Ex.
`
`1016 [MacCormack] at 52. The light activates the photosensitizer causing the
`
`generation of singlet oxygen and free radicals within the targeted skin cells.
`
`
`
`Ex. 1022 [Wachowska] at 4141-4142, Figures 1-2.
`
`37.
`
` Because singlet oxygen and free radicals are extremely reactive with
`
`biological molecules in the cell interior, their generation inside a targeted cell results
`
`in damage and cell death. Ex. 1015 [Palm] at 5; Ex. 1016 [MacCormack] at 52.
`
`38. One photosensitizer precursor compound that has been heavily studied
`
`in photodynamic therapy for the past several decades is 5-aminolevulinic acid
`
`(“ALA”). Ex. 1005 [Noven Pharma] at 1-2; Ex. 1015 [Palm] at 6; Ex. 1016
`
`[MacCormack] at 52-53. ALA is a non-proteinogenic amino acid that is found
`
`
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`endogenously in humans and other mammals that is used in the biosynthesis of
`
`heme—a precursor to hemoglobin. Ex. 1005 [Noven Pharma] at 1-2; Ex. 1015
`
`[Palm] at 6; Ex. 1016 [MacCormack] at 52-53. The heme biosynthetic pathway is
`
`depicted in the figure below:
`
`Ex. 1022 [Wachowska] at 4144, Figure 3 (with ALA and Protoporphyrin IX
`
`highlighted in yellow).
`
`
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`39.
`
` When excess ALA is applied topically, it is readily absorbed through
`
`the skin.1 Ex. 1016 [MacCormack] at 52. Compared to normal cells, cancerous cells
`
`treated with excess ALA are unable to complete the final steps in the generation of
`
`heme in the heme biosysthesis pathway. Ex. 1016 [MacCormack] at 52. As a result,
`
`protoporphyrin
`
`IX
`
`(“PPIX”)—a
`
`strong photosensitizer—accumulates
`
`in
`
`abnormal/cancerous cells. Ex. 1016 [MacCormack] at 52; Ex. 1015 [Palm] at 5-6.
`
`When the accumulated PPIX in the abnormal/cancerous cells is exposed to light,
`
`singlet oxygen and free radicals are generated within the cells, which results in cell
`
`death. Ex. 1015 [Palm] at 5; Ex. 1016 [MacCormack] at 52.
`
`40.
`
`In contrast to the abnormal/cancerous cells, healthy skin cells do not
`
`significantly accumulate PPIX. As a result, non-cancerous skin cells surrounding the
`
`diseased cells do not generate lethal amounts of reactive oxygen species and free
`
`radicals when exposed to light. Ex. 1015 [Palm] at 5-6. Therefore, ALA based
`
`photodynamic therapy can be used to preferentially kill precancerous/cancerous
`
`
`1 For photodynamic therapy applications, ALA is generally provided in its salt form
`as 5-aminolevulinic acid hydrochloride (ALA HCl). Ex. 1010 [Ameluz] at 1
`(indicating that ALA is present in Ameluz in its aminolevulinic acid hydrochloride
`form); Ex. 1011 [Levulan Label 2002] at 1 (indicating that the ALA in Levulan
`Kerastick is supplied as aminolevulinic acid HCl); Ex. 1008 [Fauteck] at 54 (stating
`that the ALA is “present as 5-aminolevulinic acid hydrochloride”); Ex. 1005 [Nove